Kinase Inhibitors Useful for the Treatment of Myleoproliferative Diseases and other Proliferative Diseases

ABSTRACT

The present invention is concerned with novel compounds useful in the treatment of hyperproliferative diseases and mammalian cancers, especially human cancers. The invention also pertains to methods of modulating kinase activities, pharmaceutical compositions, and methods of treating individuals, incorporating or using the compounds. The preferred compounds are active small molecules set forth in formulae Ia-Iww.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.11/870,388, filed Oct. 10, 2007, and claims the benefit of ProvisionalApplication 60/850,834 filed Oct. 11, 2006. These applications areincorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to novel kinase inhibitors and modulatorcompounds useful for the treatment of various diseases. Moreparticularly, the invention is concerned with such compounds, methods oftreating diseases, and methods of synthesis of the compounds.Preferrably, the compounds are useful for the modulation of kinaseactivity of C-Abl, c-Kit, VEGFR, PDGFR, Flt-3, c-MET, the HER family,the Raf kinase family and disease polymorphs thereof.

BACKGROUND OF THE INVENTION

Several members of the protein kinase family have been clearlyimplicated in the pathogenesis of various proliferative andmyeloproliferative diseases and thus represent important targets fortreatment of these diseases. Some of the proliferative diseases relevantto this invention include cancer, rheumatoid arthritis, atherosclerosis,and retinopathies. Important examples of kinases which have been shownto cause or contribute to the pathogenesis of these diseases includeC-Abl kinase and the oncogenic fusion protein bcr-Abl kinase; c-Kitkinase, c-MET, the HER family, PDGF receptor kinase, VEGF receptorkinases, Flt-3 kinase and the Raf kinase family.

C-Abl kinase is an important non-receptor tyrosine kinase involved incell signal transduction. This ubiquitously expressed kinase—uponactivation by upstream signaling factors including growth factors,oxidative stress, integrin stimulation, and ionizing radiation—localizesto the cell plasma membrane, the cell nucleus, and other cellularcompartments including the actin cytoskeleton (Van Etten, Trends CellBiol. (1999) 9: 179). There are two normal isoforms of Abl kinase:Abl-1A and Abl-1B. The N-terminal half of c-Abl kinase is important forautoinhibition of the kinase domain catalytic activity (Pluk et al, Cell(2002) 108: 247). Details of the mechanistic aspects of thisautoinhibition have recently been disclosed (Nagar et al, Cell (2003)112: 859). The N-terminal myristolyl amino acid residue of Abl-1B hasbeen shown to intramolecularly occupy a hydrophobic pocket formed fromalpha-helices in the C-lobe of the kinase domain. Such intramolecularbinding induces a novel binding area for intramolecular docking of theSH2 domain and the SH3 domain onto the kinase domain, thereby distortingand inhibiting the catalytic activity of the kinase. Thus, an intricateintramolecular negative regulation of the kinase activity is broughtabout by these N-terminal regions of c-Abl kinase. An aberrantdysregulated form of c-Abl is formed from a chromosomal translocationevent, referred to as the Philadelphia chromosome (P. C. Nowell et al,Science (1960) 132: 1497; J. D. Rowley, Nature (1973) 243: 290). Thisabnormal chromosomal translocation leads aberrant gene fusion betweenthe Abl kinase gene and the breakpoint cluster region (BCR) gene, thusencoding an aberrant protein called bcr-Abl (G. Q. Daley et al, Science(1990) 247: 824; M. L. Gishizky et al, Proc. Natl. Acad. Sci. USA (1993)90: 3755; S. Li et al, J. Exp. Med. (1999) 189: 1399). The bcr-Ablfusion protein does not include the regulatory myristolyation site (B.Nagar et al, Cell (2003) 112: 859) and as a result functions as anoncoprotein which causes chronic myeloid leukemia (CML). CML is amalignancy of pluripotent hematopoietic stem cells. The p210 form ofbcr-Abl is seen in 95% of patients with CML, and in 20% of patients withacute lymphocytic leukemia. A p185 form has also been disclosed and hasbeen linked to being causative of up to 10% of patients with acutelymphocytic leukemia.

The majority of small molecule kinase inhibitors that have been reportedhave been shown to bind in one of three ways. Most of the reportedinhibitors interact with the ATP binding domain of the active site andexert their effects by competing with ATP for occupancy. Otherinhibitors have been shown to bind to a separate hydrophobic region ofthe protein known as the “DFG-in-conformation” pocket, and still othershave been shown to bind to both the ATP domain and the“DFG-in-conformation” pocket. Examples specific to inhibitors of Rafkinases can be found in Lowinger et al, Current Pharmaceutical Design(2002) 8: 2269-2278; Dumas, J. et al., Current Opinion in Drug Discovery& Development (2004) 7: 600-616; Dumas, J. et al, WO 2003068223 A1(2003); Dumas, J., et al, WO 9932455 A1 (1999), and Wan, P. T. C., etal, Cell (2004) 116: 855-867.

Physiologically, kinases are regulated by a commonactivation/deactivation mechanism wherein a specific activation loopsequence of the kinase protein binds into a specific pocket on the sameprotein which is referred to as the switch control pocket (see WO200380110049 for further details). Such binding occurs when specificamino acid residues of the activation loop are modified for example byphosphorylation, oxidation, or nitrosylation. The binding of theactivation loop into the switch pocket results in a conformationalchange of the protein into its active form (Huse, M. and Kuriyan, J.Cell (109) 275-282).

SUMMARY OF THE INVENTION

Compounds of the present invention find utility in the treatment ofhyperproliferative diseases, mammalian cancers and especially humancancers including but not limited to malignant, melanomas,glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lungcancers, breast cancers, kidney cancers, cervical carcinomas, thyroidcancer metastasis of primary solid tumor secondary sites,myeloproliferative diseases, chronic myelogenous leukemia, acutelymphocytic leukemia, other myeloproliferative disorders, papillarythyroid carcinoma, non small cell lung cancer, mesothelioma,hypereosinophilic syndrome, gastrointestinal stromal tumors, coloniccancers, ocular diseases characterized by hyperproliferation leading toblindness including various retinopathies, i.e. diabetic retinopathy andage-related macular degeneration, rheumatoid arthritis, asthma, chronicobstructive pulmonary disorder, human inflammation, rheumatoidspondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septicshock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome,adult respiratory distress syndrome, stroke, reperfusion injury, neuraltrauma, neural ischemia, psoriasis, restenosis, chronic obstructivepulmonary disease, bone resorptive diseases, graft-versus-host reaction,Chron's disease, ulcerative colitis, inflammatory bowel disease,pyresis, and combinations thereof, a disease caused by c-Abl kinase,oncogenic forms thereof, aberrant fusion proteins thereof and polymorphsthereof, a disease caused by a Raf kinase, oncogenic forms thereof,aberrant fusion proteins thereof and polymorphs thereof, c-Kit kinase,oncogenic forms thereof, aberrant fusion proteins thereof and polymorphsthereof, Flt-3 kinase, oncogenic forms thereof, aberrant fusion proteinsthereof and polymorphs thereof, VEGFR kinase, oncogenic forms thereof,aberrant fusion proteins thereof and polymorphs thereof, PDGFR kinase,oncogenic forms thereof, aberrant fusion proteins thereof and polymorphsthereof, c-MET kinase, oncogenic forms thereof, aberrant fusion proteinsthereof and polymorphs thereof and a disease caused by a HER kinase,oncogenic forms thereof, aberrant fusion proteins thereof and polymorphsthereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following descriptions refer to various compounds and moietiesthereof.

Carbocyclyl refers to carbon rings taken from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl,norborenyl, bicyclo[2.2.2]octanyl, and bicyclo[2.2.2]octenyl;Halogen refers to fluorine, chlorine, bromine and iodine;Aryl refers to monocyclic or fused bicyclic ring systems characterizedby delocalized π electrons (aromaticity) shared among the ring carbonatoms of at least one carbocyclic ring; preferred aryl rings are takenfrom phenyl, naphthyl, tetrahydronaphthyl, indenyl, and indanyl;Heteroaryl refers to monocyclic or fused bicyclic ring systemscharacterized by delocalized π electrons (aromaticity) shared among thering carbon or heteroatoms including nitrogen, oxygen, or sulfur of atleast one carbocyclic or heterocyclic ring; heteroaryl rings are takenfrom, but not limited to, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, indolyl, indolinyl, isoindolyl, isoindolinyl,indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl,benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl,benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl,pyrazolopyridinyl, imidazolonopyridinyl, thiazolopyridinyl,thiazolonopyridinyl, oxazolopyridinyl, oxazolonopyridinyl,isoxazolopyridinyl, isothiazolopyridinyl, triazolopyridinyl,imidazopyrimidinyl, pyrazolopyrimidinyl, imidazolonopyrimidinyl,thiazolopyridiminyl, thiazolonopyrimidinyl, oxazolopyridiminyl,oxazolonopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl,triazolopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl,pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl,pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl,quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl,benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl,tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl,benzoazepinyl, benzodiazepinyl, benzoxapinyl, and benzoxazepinyl;Heterocyclyl refers to monocyclic rings containing carbon andheteroatoms taken from oxygen, nitrogen, or sulfur and wherein there isnot delocalized π electrons (aromaticity) shared among the ring carbonor heteroatoms; heterocyclyl rings include, but are not limited to,oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;Poly-aryl refers to two or more monocyclic or fused aryl bicyclic ringsystems characterized by delocalized π electrons (aromaticity) sharedamong the ring carbon atoms of at least one carbocyclic ring wherein therings contained therein are optionally linked together;Poly-heteroaryl refers to two or more monocyclic or fused bicyclicsystems characterized by delocalized π electrons (aromaticity) sharedamong the ring carbon or heteroatoms including nitrogen, oxygen, orsulfur of at least one carbocyclic or heterocyclic ring wherein therings contained therein are optionally linked together, wherein at leastone of the monocyclic or fused bicyclic rings of the poly-heteroarylsystem is taken from heteroaryl as defined broadly above and the otherrings are taken from either aryl, heteroaryl, or heterocyclyl as definedbroadly above;Poly-heterocyclyl refers to two or more monocyclic or fused bicyclicring systems containing carbon and heteroatoms taken from oxygen,nitrogen, or sulfur and wherein there is not delocalized π electrons(aromaticity) shared among the ring carbon or heteroatoms wherein therings contained therein are optionally linked, wherein at least one ofthe monocyclic or fused bicyclic rings of the poly-heteroaryl system istaken from heterocyclyl as defined broadly above and the other rings aretaken from either aryl, heteroaryl, or heterocyclyl as defined broadlyabove;Lower alkyl refers to straight or branched chain C1-C6alkyls;

Substituted in connection with a moiety refers to the fact that afurther substituent may be attached to the moiety to any acceptablelocation on the moiety.

The term salts embraces pharmaceutically acceptable salts commonly usedto form alkali metal salts of free acids and to form addition salts offree bases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts may be prepared from an inorganic acid or from an organicacid. Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriateorganic acids may be selected from aliphatic, cycloaliphatic, aromatic,arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonicacids, examples of which are formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic,phenylacetic, mandelic, embonic (pamoic), methane sulfonic,ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric andgalacturonic acid. Suitable pharmaceutically-acceptable salts of freeacid-containing compounds of the invention include metallic salts andorganic salts. More preferred metallic salts include, but are notlimited to appropriate alkali metal (group Ia) salts, alkaline earthmetal (group IIa) salts and other physiological acceptable metals. Suchsalts can be made from aluminum, calcium, lithium, magnesium, potassium,sodium and zinc. Preferred organic salts can be made from primaryamines, secondary amines, tertiary amines and quaternary ammonium salts,including in part, tromethamine, diethylamine, tetra-N-methylammonium,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine.

The term prodrug refers to derivatives of active compounds which revertin vivo into the active form. For example, a carboxylic acid form of anactive drug may be esterified to create a prodrug, and the ester issubsequently converted in vivo to revert to the carboxylic acid form.See Ettmayer et. al, J. Med. Chem., 2004, 47(10), 2393-2404 and Lorenziet. al, J. Pharm. Exp. Therpeutics, 2005, 883-8900 for reviews.

1. First Aspect of the Invention—Compounds, Methods, Preparations andAdducts

The invention includes compounds of the formula Ia:

wherein Q1 and Q2 are each individually and independently selected fromthe group consisting of N and C—Z6, provided that both Q1 and Q2 are notsimultaneously C—Z6;E1 is selected from the group consisting cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl,oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl andnaphthyl and wherein the E1 ring is substituted with one or more R16moieties and wherein the E1 ring is substituted with one or more R18moieties;wherein A is selected from the group consisting of phenyl,C3-C8carbocyclyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl,pyridinyl, pyrimidinyl, and G4;G1 is a heteroaryl taken from the group consisting of pyrrolyl, furyl,thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl;G2 is a fused bicyclic heteroaryl taken from the group consisting ofindolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl,benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl,benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl,benzimidazolonyl, benztriazolyl, imidazopyridinyl, pyrazolopyridinyl,imidazolonopyridinyl, thiazolopyridinyl, thiazolonopyridinyl,oxazolopyridinyl, oxazolonopyridinyl, isoxazolopyridinyl,isothiazolopyridinyl, triazolopyridinyl, imidazopyrimidinyl,pyrazolopyrimidinyl, imidazolonopyrimidinyl, thiazolopyridiminyl,thiazolonopyrimidinyl, oxazolopyridiminyl, oxazolonopyrimidinyl,isoxazolopyrimidinyl, isothiazolopyrimidinyl, triazolopyrimidinyl,dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyrimidinyl,phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl,pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl,quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl,benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl,tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl,benzoazepinyl, benzodiazepinyl, benzoxapinyl, and benzoxazepinyl;G3 is a non-fused bicyclic heteroaryl taken from the group consisting ofpyridylpyridiminyl pyrimidinylpyrimidinyl, oxazolylpyrimidinyl,thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl,isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl,oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl,dioxothiomorpholinylpyrimidinyl, and thiomorpholinylpyrimidinyl;G4 is a heterocyclyl taken from the group consisting of oxetanyl,azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl,imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl,piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl,tropanyl, and homotropanyl;The A ring is substituted at any substitutable position with one A1moiety, wherein A1 is selected from the group consisting of A2, A3 andA4;

A2 is selected from the group consisting of

A3 is selected from the group consisting of

A4 is selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the A ring offormula Ia; and wherein

indicates either a saturated or unsaturated bond;the A ring is optionally substituted with one or more R2 moieties;X2 is selected from the group consisting of C1-C6 alkyl, C2-C6 branchedalkyl, and a direct bond wherein E1 is directly linked to the NR3 groupof formula Ia;X3 is selected from the group consisting of —C(═O)—, —O—, —O—(CH₂)_(n)—,—S—(CH₂)_(n)—, —NR3-(CH₂)_(n)—, —O—(CH₂)_(q)—O—, —O—(CH₂)_(q)—NR3-,—N(R3)-(CH₂)_(q)—N(R3)-, —(CH₂)_(n)—N(R4)-C(═O)—,—(CH₂)_(n)—N(R4)-C(═O)(CH₂)_(n)—, —(CH₂)_(n)—C(═O)N(R4)-, —(CH₂)_(p)—,C2-C5alkenyl, C2-C5alkynyl, and C3-C6cycloalkyl and wherein the carbonatoms of —(CH₂)_(n)—, —(CH₂)_(q)—, —(CH₂)_(p)—, C2-C5alkenyl, andC2-C5alkynyl moieties of X3 may be further substituted by one or moreC1-C6alkyl;V, V1, and V2 are each independently and respectively selected from thegroup consisting of O and H₂;each Z2 is independently and individually selected from the groupconsisting of hydrogen, aryl, C1-C6alkyl, C3-C8carbocyclyl, hydroxyl,hydroxyC1-C6alkyl-, cyano, (R3)₂N—, (R4)₂N—, (R4)₂NC1-C6alkyl-,(R4)₂NC2-C6alkylN(R4)-(CH₂)_(n)—, (R4)₂NC2-C6alkylO(CH₂)_(n)—,(R3)₂NC(O)—, (R4)₂NC(O)—, (R4)₂NC(O)C1-C6alkyl-, carboxyl,carboxyC1-C6alkyl-, C1-C6alkoxycarbonyl-,C1-C6alkoxycarbonylC1-C6alkyl-, (R3)₂NSO₂—, (R4)₂NSO₂—, —SO₂R5, —SO₂R8,—(CH₂)_(n)N(R4)C(O)R8, —C(O)R8, ═O, ═NOH, ═N(OR6), —(CH₂)_(n)G1,—(CH₂)_(n)G4, —(CH₂)_(n)O(CH₂)_(n)G1, —(CH₂)_(n)O(CH₂)_(n)G4,—(CH₂)_(n)NR3(CH₂)_(n)-aryl, —(CH₂)_(n)NR3(CH₂)_(n)G1,—(CH₂)_(n)NR3(CH₂)_(n)G4, —(CH₂)_(n)NHC(O)NHS(O)₂R8,—(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O)₂R8, —(CH₂)NHC(O)(CH₂)_(n)R5,—(CH₂)_(n)NHS(O)₂R5, —(CH₂)_(n)C(O)NH(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5,—(CH₂)_(n)OC(O)R5, and —(CH₂)_(n)R5;in the event that Z2 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;each Z3 is independently and individually selected from the groupconsisting of H, C₁-C6alkyl, branched C3-C7alkyl, C3-C8-carbocyclyl,halogen, fluoroC1-C6alkyl wherein the alkyl moiety can be partially orfully fluorinated, cyano, hydroxyl, methoxy, oxo, (R3)₂NC(O)—,(R4)₂NC(O)—, —N(R4)C(O)R8, (R3)₂NSO₂—, (R4)₂NSO₂—, —N(R4)SO₂R5,—N(R4)SO₂R8, —(CH₂)_(n)N(R3)₂, —(CH₂)_(n)N(R4)₂, —O(CH₂)_(q)N(R4)₂,—O(CH₂)_(q)O—C1-C6alkyl, —N(R3)(CH₂)_(q)O—C1-C6alkyl,—N(R3)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)R5, —NR3(CH₂)_(q)R5, —C(O)R5, —C(O)R8,—R5, and nitro;in the event that Z3 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;each Z4 is independently and individually selected from the groupconsisting of H, C₁-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl-,(R4)₂N—C2-C6alkyl-, (R4)₂N—C2-C6alkylN(R4)-C2-C6alkyl-,(R4)₂N—C2-C6alkyl-O—C2-C6alkyl-, (R4)₂NC(O)—C1-C6alkyl-,carboxyC1-C6alkyl-, C1-C6alkoxycarbonylC1-C6alkyl-,—C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO₂R8, —COR8, —(CH₂)_(n)G1,—(CH₂)_(n)G4, —(CH₂)_(q)—O(CH₂)_(n)G1, —(CH₂)_(q)O(CH₂)_(n)G4,—(CH₂)_(q)NR3(CH₂)_(n)G1, —(CH₂)_(q)NR3(CH₂)_(n)G4,—(CH₂)_(q)NHC(O)(CH₂)_(n)R5, —(CH₂)_(q)C(O)NH(CH₂)_(q)R5,—(CH₂)_(q)C(O)R5, —(CH₂)_(q)OC(O)R5, —(CH₂)_(q)R5,—(CH₂)_(q)NR4(CH₂)_(q)R5, and —(CH₂)_(q)O(CH₂)_(q)R5;in the event that Z4 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;each Z6 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl,hydroxyC1-C6alkyl, hydroxyC2-C6 branched alkyl-, C1-C6alkoxy,C1-C6alkoxyC1-C6alkyl-, C1-C6alkoxyC2-C6 branched alkyl-, branchedC2-C6alkoxy-, C1-C6alkylthio, (R3)₂N—, —N(R3)COR8, (R4)₂N—, —R5,—N(R4)C(O)R8, —N(R3)SO₂R6, —C(O)N(R3)₂, —C(O)N(R4)₂, —C(O)R5, —SO₂NHR4,halogen, fluoroC1-C6alkyl wherein the alkyl is fully or partiallyfluorinated, cyano, fluoroC1-C6alkoxy wherein the alkyl is fully orpartially fluorinated, —O(CH₂)_(q)N(R4)₂, —N(R3)(CH₂)_(q)N(R4)₂,—O(CH₂)_(q)O—C1-C6alkyl, —O(CH₂)_(q)N(R4)₂,—N(R3)(CH₂)_(q)O-DC1-C6alkyl, —N(R3)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)R5, and—N(R3)(CH₂)_(q)R5, —(NR3)_(r)R17, —(O)_(r)R17, —(S)_(r)R17,—(CH₂)_(n)R17, —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(q)O(CH₂)_(n)G1,—(CH₂)_(q)O(CH₂)_(n)G4, —(CH₂)_(q)N(R3)(CH₂)_(n)G1, and—(CH₂)_(q)NR3(CH₂)_(n)G4;each R2 is selected from the group consisting of Z3-substituted aryl,Z3-substituted G1, Z3-substituted G4, C1-C6alkyl, branched C3-C8alkyl,R19 substituted C3-C8carbocyclyl, hydroxylC1-C6alky, hydroxyl branchedC3-C6alkyl-, hydroxyl substituted C3-C8carbocyclyl-, cyanoC1-C6 alkyl-,cyano substituted branched C3-C6alkyl-, cyano substitutedC3-C8carbocyclyl-, (R4)₂NC(O)C1-C6alkyl-, (R4)₂NC(O) substitutedbranched C3-C6alkyl-, (R4)₂NC(O) substituted C3-C8-carbocyclyl-,fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated,halogen, cyano, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein the alkylgroup is fully or partially fluorinated;each R3 is independently and individually selected from the groupconsisting of H, C₁-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, andZ3-substituted phenyl-;each R4 is independently and individually selected from the groupconsisting of H, C₁-C₆alkyl, hydroxyC1-C6alkyl-, dihydroxyC1-C6alkyl-,C1-C6alkoxyC1-C6alkyl-, branched C3-C7alkyl-, branchedhydroxyC1-C6alkyl-, branched C1-C6alkoxyC1-C6alkyl-, brancheddihydroxyC2-C6alkyl-, —(CH₂)_(p)N(R7)₂, —(CH₂)_(p)R5,—(CH₂)_(p)C(O)N(R7)₂, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3,C3-C8-carbocyclyl, hydroxyl substituted C3-C8carbocyclyl-, alkoxysubstituted C3-C8carbocyclyl-, dihydroxyl substituted C3-C8carbocyclyl-, and —(CH₂)_(n)R17;each R5 is independently and individually selected from the groupconsisting of

and wherein the symbol (##) is the point of attachment of the R5 moiety;each R6 is independently and individually selected from the groupconsisting of C₁-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, phenyl,G1, and G4;each R7 is independently and individually selected from the groupconsisting of H, C₁-C₆alkyl, hydroxyC2-C6alkyl-, dihydroxyC2-C6alkyl-,C2-C6alkoxyC2-C6alkyl-, branched C3-C7alkyl-, branched hydroxyC2-C6alkyl-, branched C2-C6alkoxyC2-C6alkyl-, branched dihydroxyC2-C6alkyl-,—(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3, C3-C8-carbocyclyl,hydroxyl substituted C3-C8carbocyclyl-, alkoxy substitutedC3-C8carbocyclyl-, dihydroxy substituted C3-C8carbocyclyl, and—(CH₂)_(n)R17;each R8 is independently and individually selected from the groupconsisting of C₁-C6alkyl, branched C3-C7alkyl, fluoroC1-C6alkyl whereinthe alkyl moiety is partially or fully fluorinated, C3-C8carbocyclyl,Z3-substituted phenyl-, Z3-substituted phenylC₁-C6alkyl-, Z3-substitutedG1-, Z3-substituted G1-C1-C6alkyl-, Z2-substituted G4-, Z2-substitutedG4-C1-C6alkyl-, OH, C1-C6alkoxy, N(R3)₂, N(R4)₂, and R5;each R9 is independently and individually selected from the groupconsisting of H, F, C₁-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl,phenyl, phenyl-C1-C6alkyl-, —(CH₂)_(n)G1, and —(CH₂)_(n)G4;each R10 is independently and individually selected from the groupconsisting of CO₂H, CO₂C1-C6alkyl, —C(O)N(R4)₂, OH, C1-C6alkoxy, and—N(R4)₂;

each R13 is independently and individually selected from the groupconsisting of H, C₁-C6alkyl, branched C3-C7alkyl, carbocyclyl,hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl-, (R4)₂NC(O)—,(R4)₂NC(O)C1-C6alkyl-, carboxyC1-C6alkyl-, C₁-C₆alkoxycarbonyl-,C1-C6alkoxycarbonylC1-C6alkyl-, (R4)₂N—C2-C6alkyl-,(R4)₂N—C2-C6alkylN(R4)(CH₂)_(q)—, R5-C2-C6alkylN(R4)(CH₂)_(q)—,(R4)₂N—C2-C6alkylO(CH₂)_(q)—, R5-C2-C6alkylO(CH₂)_(q)—,—(CH₂)_(q)N(R4)C(O)R8, aryl, arylC1-C6alkyl, aryloxyC2-C6alkyl-,arylaminoC2-C6alkyl-, C1-C6alkoxycarbonylC1-C6alkyl-,—C2-C6alkylN(R4)C(O)R8, R8C(═NR3)-, —SO₂R8, —COR8, —(CH₂)_(n)G1,—(CH₂)_(n)-G4, —(CH₂)_(n))(CH₂)_(n)G1, —(CH₂)_(n)O(CH₂)_(n)G4,—(CH₂)_(n)N(R3)(CH₂)_(n)G1, and —(CH₂)_(n)N(R3)(CH₂)_(n)G4;

each R14 is independently and respectively selected from the groupconsisting of H, C₁-C6alkyl, branched C3-C6alkyl, and C3-C7-carbocyclyl;each R16 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, C₃-C₈ carbocyclyl,halogen, fluoro C1-C6alkyl wherein the alkyl moiety can be partially orfully fluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxywherein the alkyl moiety can be partially or fully fluorinated, —N(R3)₂,—N(R4)₂, and nitro;each R17 is taken from the group comprising phenyl, naphthyl, pyrrolyl,furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,pyrazinyl, pyridazinyl, triazinyl, oxetanyl, azetadinyl,tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl, diazepinyl,pyrrolidinyl, and piperidinyl;wherein R17 can be further substituted with one or more Z2, Z3 or Z4moieties;R18 is independently and individually selected from the group consistingof hydrogen, C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen,fluoroC1-C6alkyl wherein the alkyl moiety can be partially or fullyfluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy wherein thealkyl moiety can be partially or fully fluorinated, —N(R3)₂, —N(R4)₂,C2-C₃alkynyl, and nitro;R19 is H or C1-C6alkyl;wherein two R3 or R4 moieties are independently and individually takenfrom the group consisting of C1-C6alkyl and branched C3-C6alkyl,hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogenatom, said moieties may cyclize to form a C3-C7 heterocyclyl ring;and n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3, v is 1 or 2;with the proviso that compounds of formula Ia can not be

1.1 Compounds of Formula Ia which Exemplify Preferred A and X2-E1Moieties

In a preferred embodiment of compounds of formula Ia, said compoundshave structures of formula I-Ib:

wherein the A ring is pyrazolyl.

1.1.1 Compounds of Formula I-1b which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-1b, said compoundshave structures of formula I-1c:

1.1.2 Compounds of Formula Ib which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-1b, said compoundshave structures of formula I-1d

1.1.3 Compounds of Formula I-1b which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-1b, said compoundshave structures of formula I-1e

1.1.4 More Preferred Compounds of Section 1.1

In a preferred embodiment of compounds from Section 1.1, said compoundshave structures of formula I-1f:

1.1.5 Compounds of Section 1.1.4 with Preferred R16 Moieties

In a preferred embodiment of compounds from Section 1.1.4, saidcompounds have structures of formula I-1g:

1.1.6 Compounds of Section 1.1.5 with a More Preferred A1 Moieties

In a more preferred embodiment of compounds from Section 1.1.5, saidcompounds have structures of formula I-1 h:

Wherein A1 is selected from the group consisting of

1.1.7 Compounds of Section 1.1.5 with a More Preferred Z6 Moieties

In a more preferred embodiment of compounds from Section 1.1.5, saidcompounds have structures of formula I-1i:

wherein Z6 is —C(O)NHR4, —NHR4 or R19 substituted pyrazole;

1.2 Compounds of Formula Ia which Exemplify Preferred A and X2-E1Moieties

In a preferred embodiment of compounds of formula Ia, said compoundshave structures of formula I-2a:

Where in the A ring is isoxazolyl.

1.2.1 Compounds of Formula I-2a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-2a, said compoundshave structures of formula I-2b:

1.2.2 Compounds of Formula I-2a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-2a, said compoundshave structures of formula I-2c:

1.2.3 Compounds of Formula I-2a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-2a, said compoundshave structures of formula I-2d:

1.2.4 More Preferred Compounds of Section 1.2

In a preferred embodiment of compounds from Section 1.2, said compoundshave structures of formula I-2e:

1.2.5 Compounds of Section 1.2.4 with Preferred R16 Moieties

In a preferred embodiment of compounds from Section 1.2.4, saidcompounds have structures of formula I-2f:

1.2.6 Compounds of Section 1.2.5 with a more Preferred A1 Moieties

In a more preferred embodiment of compounds from Section 1.2.5, saidcompounds have structures of formula I-2g:

Wherein A1 is selected from the group consisting of

1.2.7 Compounds of Section 1.2.5 with a More Preferred Z6 Moieties

In a more preferred embodiment of compounds from Section 1.2.5, saidcompounds have structures of formula I-2h:

wherein Z6 is —C(O)NHR4, —NHR4 or R19 substituted pyrazole;

1.3 Compounds of Formula Ia which Exemplify Preferred A and X2-E1Moieties

In a preferred embodiment of compounds of formula Ia, said compoundshave structures of formula I-3a:

wherein the A ring is thienyl.

1.3.1 Compounds of Formula I-3a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-3a, said compoundshave structures of formula I-3b:

1.3.2 Compounds of Formula Ix which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-3a, said compoundshave structures of formula I-3c:

1.3.3 Compounds of Formula I-3a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-3a, said compoundshave structures of formula I-3d:

1.3.4 More Preferred Compounds of Section 1.3

In a preferred embodiment of compounds from Section 1.3, said compoundshave structures of formula I-3e:

1.3.5 Compounds of Section 1.3.4 with Preferred R16 Moieties

In a preferred embodiment of compounds from Section 1.3.4, saidcompounds have structures of formula I-3f:

1.3.6 Compounds of Section 1.3.5 with a More Preferred A1 Moieties

In a more preferred embodiment of compounds from Section 1.3.5, saidcompounds have structures of formula I-3g:

Wherein A1 is selected from the group consisting of

1.3.7 Compounds of Section 1.3.5 with a More Preferred Z6 Moieties

In a more preferred embodiment of compounds from Section 1.3.5, saidcompounds have structures of formula I-3h:

wherein Z6 is —C(O)NHR4, —NHR4 or R19 substituted pyrazole;

1.4 Compounds of Formula Ia which Exemplify Preferred A and X2-E1Moieties

In a preferred embodiment of compounds of formula Ia, said compoundshave structures of formula I-4-a:

wherein the A ring is furyl.

1.4.1 Compounds of Formula Iii which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-4-a, said compoundshave structures of formula I-4-b:

1.4.2 Compounds of Formula Iii which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-4-a, said compoundshave structures of formula I-4-c:

1.4.3 Compounds of Formula Im which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-4-a, said compoundshave structures of formula I-4-d:

1.4.4 More Preferred Compounds of Section 1.4

In a preferred embodiment of compounds from Section 1.4, said compoundshave structures of formula I-4-e:

1.4.5 Compounds of Section 1.4.4 with Preferred R16 Moieties

In a preferred embodiment of compounds from Section 1.4.4, saidcompounds have structures of formula I-4-f:

1.4.6 Compounds of Section 1.4.5 with a More Preferred A1 Moieties

In a more preferred embodiment of compounds from Section 1.4.5, saidcompounds have structures of formula I-4-g:

Wherein A1 is selected from the group consisting of

1.4.7 Compounds of Section 1.4.5 with a More Preferred Z6 Moieties

In a more preferred embodiment of compounds from Section 1.4.5, saidcompounds have structures of formula I-4-h:

wherein Z6 is —C(O)NHR4, —NHR4 or R19 substituted pyrazole;

1.5 Compounds of Formula Ia which Exemplify Preferred A and X2-E1Moieties

In a preferred embodiment of compounds of formula Ia, said compoundshave structures of formula I-5a:

wherein the A ring is pyrrolyl.

1.5.1 Compounds of Formula I-5a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-5a, said compoundshave structures of formula I-5b:

1.5.2 Compounds of Formula I-5a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-5a, said compoundshave structures of formula I-5c:

1.5.3 Compounds of Formula-5a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-5a, said compoundshave structures of formula I-5d:

1.5.4 More Preferred Compounds of Section 1.5

In a preferred embodiment of compounds from Section 1.5, said compoundshave structures of formula I-5e:

1.5.5 Compounds of Section 1.5.4 with Preferred R16 Moieties

In a preferred embodiment of compounds from Section 1.5.4, saidcompounds have structures of formula I-5f:

1.5.6 Compounds of Section 1.5.5 with a More Preferred A1 Moieties

In a more preferred embodiment of compounds from Section 1.5.5, saidcompounds have structures of formula I-5g:

Wherein A1 is selected from the group consisting of

1.5.7 Compounds of Section 1.5.5 with a More Preferred Z6 Moieties

In a more preferred embodiment of compounds from Section 1.5.5, saidcompounds have structures of formula I-5h:

wherein Z6 is —C(O)NHR4, —NHR4 or R19 substituted pyrazole;

1.6 Compounds of Formula Ia which Exemplify Preferred A and X2-E1Moieties

In a preferred embodiment of compounds of formula Ia, said compoundshave structures of formula I-6a:

wherein the A ring is imidazolyl.

1.6.1 Compounds of Formula I-6a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-6a, said compoundshave structures of formula I-6b:

1.6.2 Compounds of Formula I-6a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-6a, said compoundshave structures of formula I-6c:

1.6.3 Compounds of Formula I-6a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-6a, said compoundshave structures of formula I-6d:

1.6.4 More Preferred Compounds of Section 1.6

In a preferred embodiment of compounds from Section 1.6, said compoundshave structures of formula I-6e:

1.6.5 Compounds of Section 1.6.4 with Preferred R16 Moieties

In a preferred embodiment of compounds from Section 1.6.4, saidcompounds have structures of formula I-6f:

1.6.6 Compounds of Section 1.6.5 with a More Preferred A1 Moieties

In a more preferred embodiment of compounds from Section 1.6.5, saidcompounds have structures of formula I-6g:

Wherein A1 is selected from the group consisting of

1.6.7 Compounds of Section 1.6.5 with a More Preferred Z6 Moieties

In a more preferred embodiment of compounds from Section 1.6.5, saidcompounds have structures of formula I-6h:

wherein Z6 is —C(O)NHR4, —NHR4 or R19 substituted pyrazole;

1.7 Compounds of Formula Ia which Exemplify Preferred A and X2-E1Moieties

In a preferred embodiment of compounds of formula Ia, said compoundshave structures of formula I-7a:

wherein the A ring is thiazolyl.

1.7.1 Compounds of Formula I-7a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-7a, said compoundshave structures of formula I-7b:

1.7.2 Compounds of Formula I-7a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-7a, said compoundshave structures of formula I-7c:

1.7.3 Compounds of Formula I-7a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-7a, said compoundshave structures of formula I-7d:

1.7.4 More Preferred Compounds of Section 1.7

In a preferred embodiment of compounds from Section 1.7, said compoundshave structures of formula I-7e:

1.7.5 Compounds of Section 1.7.4 with Preferred R16 Moieties

In a preferred embodiment of compounds from Section 1.7.4, saidcompounds have structures of formula I-7f:

1.7.6 Compounds of Section 1.7.5 with a More Preferred A1 Moieties

In a more preferred embodiment of compounds from Section 1.7.5, saidcompounds have structures of formula I-7g:

Wherein A1 is selected from the group consisting of

1.7.7 Compounds of Section 1.7.5 with a More Preferred Z6 Moieties

In a more preferred embodiment of compounds from Section 1.7.5, saidcompounds have structures of formula I-7h:

wherein Z6 is —C(O)NHR4, —NHR4 or R19 substituted pyrazole;

1.8 Compounds of Formula Ia which Exemplify Preferred A and X2-E1Moieties

In a preferred embodiment of compounds of formula Ia, said compoundshave structures of formula I-8a:

wherein the A ring is oxazolyl.

1.8.1 Compounds of Formula I-8a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-8a, said compoundshave structures of formula I-8b:

1.8.2 Compounds of Formula I-8a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-8a, said compoundshave structures of formula I-8c:

1.8.3 Compounds of Formula I-8a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-8a, said compoundshave structures of formula I-8d:

1.8.4 More Preferred Compounds of Section 1.8

In a preferred embodiment of compounds from Section 1.8, said compoundshave structures of formula I-8e:

1.8.5 Compounds of Section 1.8.4 with Preferred R16 Moieties

In a preferred embodiment of compounds from Section 1.8.4, saidcompounds have structures of formula I-8f:

1.8.6 Compounds of Section 1.8.5 with a More Preferred A1 Moieties

In a more preferred embodiment of compounds from Section 1.8.5, saidcompounds have structures of formula I-8g:

Wherein A1 is selected from the group consisting of

1.8.7 Compounds of Section 1.8.5 with a More Preferred Z6 Moieties

In a more preferred embodiment of compounds from Section 1.8.5, saidcompounds have structures of formula I-8h:

wherein Z6 is —C(O)NHR4, —NHR4 or R19 substituted pyrazole;

1.9 Compounds of Formula Ia which Exemplify Preferred A and X2-E1Moieties

In a preferred embodiment of compounds of formula Ia, said compoundshave structures of formula I-9a:

wherein the A ring is isothiazolyl.

1.9.1 Compounds of Formula I-9a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-9a, said compoundshave structures of formula I-9b:

1.9.2 Compounds of Formula-9a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-9a, said compoundshave structures of formula I-9c:

1.9.3 Compounds of Formula I-9a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-9a, said compoundshave structures of formula I-9d:

1.9.4 More Preferred Compounds of Section 1.9

In a preferred embodiment of compounds from Section 1.9, said compoundshave structures of formula I-9e:

1.9.5 Compounds of Section 1.9.4 with Preferred R16 Moieties

In a preferred embodiment of compounds from Section 1.9.4, saidcompounds have structures of formula I-9f:

1.9.6 Compounds of Section 1.9.5 with a More Preferred A1 Moieties

In a more preferred embodiment of compounds from Section 1.9.5, saidcompounds have structures of formula I-9g:

Wherein A1 is selected from the group consisting of

1.9.7 Compounds of Section 1.9.5 with a More Preferred Z6 Moieties

In a more preferred embodiment of compounds from Section 1.9.5, saidcompounds have structures of formula I-9h:

wherein Z6 is —C(O)NHR4, —NHR4 or R19 substituted pyrazole;

1.10 Compounds of Formula Ia which Exemplify Preferred A and X2-E1Moieties

In a preferred embodiment of compounds of formula Ia, said compoundshave structures of formula I-10a:

wherein the A ring is phenyl.

1.10.1 Compounds of Formula I-10a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-10a, said compoundshave structures of formula I-10b:

1.10.2 Compounds of Formula I-10a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-10a, said compoundshave structures of formula I-10c:

1.10.3 Compounds of Formula I-10a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-10a, said compoundshave structures of formula I-10d:

1.10.4 More Preferred Compounds of Section 1.10

In a preferred embodiment of compounds from Section 1.10, said compoundshave structures of formula I-10e:

1.10.5 Compounds of Section 1.10.4 with Preferred R16 Moieties

In a preferred embodiment of compounds from Section 1.10.4, saidcompounds have structures of formula I-10f:

1.10.6 Compounds of Section 1.10.5 with a More Preferred A1 Moieties

In a more preferred embodiment of compounds from Section 1.10.5, saidcompounds have structures of formula I-10g:

Wherein A1 is selected from the group consisting of

1.10.7 Compounds of Section 1.10.5 with a More Preferred Z6 Moieties

In a more preferred embodiment of compounds from Section 1.10.5, saidcompounds have structures of formula I-10h:

wherein Z6 is —C(O)NHR4, —NHR4 or R19 substituted pyrazole;

1.11 Compounds of Formula Ia which Exemplify Preferred A and X2-E1Moieties

In a preferred embodiment of compounds of formula Ia, said compoundshave structures of formula I-11a:

wherein the A ring is pyrimidinyl.

1.11.1 Compounds of Formula I-11a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-11a, said compoundshave structures of formula I-11b:

1.11.2 Compounds of Formula I-11a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-11a, said compoundshave structures of formula I-11c:

1.11.3 Compounds of Formula I-11a which exemplify preferred A1 Moieties

In a preferred embodiment of compounds of formula I-11a, said compoundshave structures of formula I-11d:

1.11.4 More Preferred Compounds of Section 1.11

In a preferred embodiment of compounds from Section 1.11, said compoundshave structures of formula I-11e:

1.11.5 Compounds of Section 1.11.4 with Preferred R16 Moieties

In a preferred embodiment of compounds from Section 1.11.4, saidcompounds have structures of formula I-11f:

1.11.6 Compounds of Section 1.11.5 with a More Preferred A1 Moieties

In a more preferred embodiment of compounds from Section 1.11.5, saidcompounds have structures of formula I-11g:

Wherein A1 is selected from the group consisting of

1.11.7 Compounds of Section 1.11.5 with a More Preferred Z6 Moieties

In a more preferred embodiment of compounds from Section 1.11.5, saidcompounds have structures of formula I-11h:

wherein Z6 is —C(O)NHR4, —NHR4 or R19 substituted pyrazole;

1.12 Compounds of Formula Ia which Exemplify Preferred A and X2-E1Moieties

In a preferred embodiment of compounds of formula Ia, said compoundshave structures of formula I-12a:

wherein the A ring is pyridinyl.

1.12.1 Compounds of Formula I-12a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-12a, said compoundshave structures of formula I-12b:

1.12.2 Compounds of Formula I-12a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-12a, said compoundshave structures of formula I-12c:

1.12.3 Compounds of Formula I-12a which Exemplify Preferred A1 Moieties

In a preferred embodiment of compounds of formula I-12a, said compoundshave structures of formula I-12d:

1.12.4 More Preferred Compounds of Section 1.12

In a preferred embodiment of compounds from Section 1.12, said compoundshave structures of formula I-12e:

1.12.5 Compounds of Section 1.12.4 with Preferred R16 Moieties

In a preferred embodiment of compounds from Section 1.12.4, saidcompounds have structures of formula I-12f:

1.12.6 Compounds of Section 1.12.5 with a More Preferred A1 Moieties

In a more preferred embodiment of compounds from Section 1.12.5, saidcompounds have structures of formula I-12g:

Wherein A1 is selected from the group consisting of

1.12.7 Compounds of Section 1.12.5 with a More Preferred Z6 Moieties

In a more preferred embodiment of compounds from Section 112.5, saidcompounds have structures of formula I-12h:

wherein Z6 is —C(O)NHR4, —NHR4 or R19 substituted pyrazole;

1.13 Methods 1.13a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of avariety of kinases, e.g. C-Abl kinase, bcr-Abl kinase, Flt-3, c-Kit,PDGFR, VEGFR, c-MET, the HER family of kinases and the Raf family ofkinases. The kinases may be wildtype kinases, oncogenic forms thereof,aberrant fusion proteins thereof or polymorphs of any of the foregoing.The method comprises the step of contacting the kinase species withcompounds of the invention and especially those set forth in sections1.1-1.12. The kinase species may be activated or unactivated, and thespecies may be modulated by phosphorylations, sulfation, fatty acidacylations glycosylations, nitrosylation, cystinylation (i.e. proximalcysteine residues in the kinase react with each other to form adisulfide bond) or oxidation. The kinase activity may be selected fromthe group consisting of catalysis of phospho transfer reactions,inhibition of phosphorylation, oxidation or nitrosylation of said kinaseby another enzyme, enhancement of dephosphorylation, reduction ordenitrosylation of said kinase by another enzyme, kinase cellularlocalization, and recruitment of other proteins into signaling complexesthrough modulation of kinase conformation.

1.13b Treatment Methods

The methods of the invention also include treating individuals sufferingfrom a condition selected from the group consisting of cancer andhyperproliferative diseases. These methods comprise administering tosuch individuals compounds of the invention, and especially those ofsections 1.1-1.12, said diseases including, but not limited to, adisease caused by c-Abl kinase, oncogenic forms thereof, aberrant fusionproteins thereof and polymorphs thereof, chronic myelogenous leukemia,acute lymphocytic leukemia, other myeloproliferative disorders,gastrointestinal stromal tumors, age-related macular degeneration,hypereosinophilic syndrome, glioblastomas, ovarian cancer, pancreaticcancer, prostate cancer, lung cancers, breast cancers, kidney cancers,cervical carcinomas, metastasis of primary solid tumor secondary sites,ocular diseases characterized by hyperproliferation leading to blindnessincluding various retinopathies, i.e. diabetic retinopathy andage-related macular degeneration, rheumatoid arthritis, melanomas, coloncancer, thyroid cancer, a disease caused by a mutation in theRAS-RAF-MEK-ERK-MAP kinase pathway, human inflammation, rheumatoidspondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septicshock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome,adult respiratory distress syndrome, stroke, reperfusion injury, neuraltrauma, neural ischemia, psoriasis, restenosis, chronic obstructivepulmonary disease, bone resorptive diseases, graft-versus-host reaction,Chron's disease, ulcerative colitis, inflammatory bowel disease,pyresis, and combinations thereof. The administration method is notcritical, and may be from the group consisting of oral, parenteral,inhalation, and subcutaneous.

1.14 Pharmaceutical Preparations

The compounds of the invention, especially those of sections 1.1-1.12,may form a part of a pharmaceutical composition by combining one or moresuch compounds with a pharmaceutically acceptable carrier. Additionally,the compositions may include an additive selected from the groupconsisting of adjuvants, excipients, diluents, and stabilizers.

2. Synthesis of Compounds of the Present Invention

The compounds of the invention are available by the procedures andteachings of WO 2006/071940, filed Dec. 23, 2005, incorporated byreference, and by the general synthetic methods illustrated in theschemes below and the accompanying examples.

As indicated in Scheme 1, ureas of general formula 1 can be readilyprepared by the union of amines of general formula 2 with isocyanates 3or isocyanate surrogates 4 (trichloroethyl carbamates) or 5 (isopropenylcarbamates). Preferred conditions for the preparation of compounds ofgeneral formula 1 involve heating a solution of 4 or 5 with 2 in thepresence of a tertiary base such as diisopropylethylamine, triethylamineor N-methylpyrrolidine in a solvent such as dimethylformamide,dimethylsulfoxide, tetrahydrofuran or 1,4-dioxane at a temperaturebetween 50 and 100° C. for a period of time ranging from 1 hour to 2days.

As shown in Scheme 2, isocyanates 3 can be prepared from amines A-NH₂ 6with phosgene, or a phosgene equivalent such as diphosgene, triphosgene,or N,N-dicarbonylimidazole. Trichloroethyl carbamates 4 and isopropenylcarbamates 5 are readily prepared from amines A-NH₂ (6) by acylationwith trichloroethyl chloroformate or isopropenyl chloroformate bystandard conditions familiar to those skilled in the art. Preferredconditions for the preparation of 4 and 5 include include treatment ofcompound 6 with the appropriate chloroformate in the presence ofpyridine in an aprotic solvent such as dichloromethane or in thepresence of aqueous hydroxide or carbonate in a biphasic aqueous/ethylacetate solvent system.

Additionally, compounds of formula 1 can also be prepared fromcarboxylic acids 7 by the intermediacy of in-situ generated acyl azides(Curtius rearrangement) as indicated in Scheme 3. Preferred conditionsfor Scheme 3 include the mixing of acid 7 with amine 2 anddiphenylphosphoryl azide in a solvent such as 1,4-dioxane ordimethylformamide in the presence of base, such as triethylamine, andraising the temperature of the reaction to about 80-120° C. to affectthe Curtius rearrangement.

Many methods exist for the preparation of amines A-NH₂ 6 and acidsA-CO₂H 7, depending on the nature of the A-moiety. Many such methodshave been described in detail in WO 2006/071940, and are incorporated byreference here. Preferred synthetic methods are outlined in thefollowing schemes for the non-limiting examples wherein A is a1-substituted-pyrazole (optionally substituted by R2) or A and A1 arelinked by C—C bond.

As illustrated in Scheme 4, A1-substituted, pyrazole amines 10 (apreferred aspect of A-NH₂ 6, Scheme 2) are available by the condensationof hydrazines 8 and beta-keto nitriles 9. Preferred conditions for thistransformation are by heating in ethanolic HCl. Hydrazines 8 are in turnavailable by the diazotization of amines 11 followed by reduction or,alternately from the hydrolysis of hydrazones 13 obtained by thepalladium mediated coupling of benzophenone hydrazone with compounds offormula A1-X 12, wherein X represents a halogen or triflate moiety.

A non-limiting example of Scheme 4 is illustrated by the preparation ofcompound 19 (Scheme 5 and the accompanying examples). Thus commerciallyavailable 6-hydroxyquinoline 14 can be converted totrifluoromethanesulfonate 15 by treatment with triflic anhydride andpyridine. Reaction of 15 with benzophenone hydrazone in the presence ofa palladium catalyst, preferably a catalyst containing thebis(diphenylphosphino)ferrocene ligand, provides the hydrazone 16.Reaction of 16 with ethanolic HCl at reflux provides the hydrazine 17,which can be combined with keto nitriles of general formula 18 byfurther heating in ethanolic HCl to provide quinoline pyrazole amines offormula 19. In another aspect of this synthetic sequence, hydrazone 16can be converted directly to pyrazole 19 by the direct reaction withketo nitrile 18 upon heating in ethanolic HCl.

Another preferred method for constructing A1-substituted pyrazoles isillustrated by the general preparation of pyrazole acid 22 (Scheme 6),an aspect of A-CO₂H 7 (Scheme 3). As indicated in Scheme 6, the union ofa pyrazole 5-carboxylic ester 20 with A1-X 12, wherein X reprepesents ahalide, triflate, or boronic acid suitable for direct transitionmetal-catalyzed couplings with pyrazoles 20, provides A1-substitutedpyrazole esters 21. Preferred conditions for such transformationsinvolve mixing a boronic acid 11 [X═B(OH)₂] and esters 20 indichloromethane with copper acetate and pyridine in the presence ofcrushed molecular sieves, with or without heating. Preferred esters forthis transformation include ethyl, tert-butyl and benzyl esters. Theesters 21 in turn can be converted to acids 22 by standard conditionsfamiliar to those skilled in the art, such as saponification, acidichydrolysis or hydrogenation.

The synthesis of intermediates useful for the construction of compoundsof formula 1 wherein A and A1 are linked by a C—C bond is shown inScheme 7. In this case, palladium catalyzed reactions (for example,Suzuki or Stille reactions) of A1-X 12 with a complementary component 23or 24 provides compounds 25 or 26, examples of general intermediatesA-NH₂ 6 or A-CO₂H 7, respectively. In this synthetic sequence, theX-groups on the reactants 12 and 23 or 24 are moieties that undergotransition metal catalyzed cross coupling reactions, such as halides ortriflates and boronic acids or esters, stannanes, silanes, organozincsor other organometallic moieties known by those skilled in the art to besuitable substrates for such processes. The X-groups in Scheme 7 arecomplementary moieties for cross coupling processes such that when A1-X12 is a halide or triflate, A-X 23 or A-X 24 will be a complementaryorganometallic, such as a stannane or the like or a boronic acid orester. Likewise, if A1-X 12 is an organometallic reagent or a boronicacid or ester, A-X will be a halide or triflate.

Within Scheme 7, it will be understood by those skilled in the art thatthere are additional synthetic equivalents for the Y-groups of 23 and 24that can be used interchangeably with NH₂ and CO₂H with the addition ofadditional transforming steps. For example, the Y group of 23 might alsobe a protected amino group such as N-Boc or a surrogate amino group suchas nitro that would give rise to compounds of formula 25 after acidichydrolysis or reduction respectively. Similarly, it will be recognizedthat the Y group of 24 might also be an ester or nitrile which could behydrolyzed to an acid of formula 26 by standard synthetic methods.

A non limiting example of Scheme 7 is illustrated by the preparation ofcompound 29, an example of general intermediate A-NH₂ 6, above. Thus,commercially available quinoline 6-boronic acid 27 can be combined withcommercially available 5-fluoro-2-iodoaniline 28 in the presence of apalladium catalyst to provide compound 29, an example of generalintermediate A-NH₂ 6, above.

Amines 2 (Schemes 1 and 3, above) useful for the invention can besynthesized according to methods commonly known to those skilled in theart. Non-limiting examples are illustrated in the following schemes. Ageneral preparation of aryl amine 32, an example of amine 2, above, isshown in Scheme 9. Thus, chloropyridines of formula 31 are reacted withphenols of formula 30 in the presence of base such as potassiumtert-butoxide. Reactions are generally conducted at temperatures between0° C. and 150° C. in solvents such as dimethylacetamide,dimethylformamide or dimethylsulfoxide. Some non-limiting examples ofgeneral synthetic Scheme 9 are shown in Schemes 10-12, below.

In Scheme 10, commercially available 3-fluoro-4-aminophenol is reactedwith potassium tert-butoxide and chloropyridines 34 or 35 to provideamino ethers 36 and 37 respectively. The preferred solvent for thistransformation is dimethylacetamide at a temperature between 80 and 100°C.

In a similar manner, commercially available 2-methyl-4-aminophenol 38 iscombined with chloropyridines 34 and 35 to provide amino ethers 39 and40, respectively (Scheme 11).

Scheme 12 illustrates the preparation of meta-substituted pyridyl etheramines 47 and 48, examples of general intermediate 2, above. As shown inScheme 12, commercially available 2-chloro-4-fluorophenol 41 is treatedwith methyl chloroformate to provide carbonate 42. Nitration understandard conditions then provides adduct 43. Hydrolysis of the carbonateprovides phenol 44. Concomitant reduction of both the nitro and chloromoieties provides aminophenol 45. Treatment of phenol 45 sequentiallywith potassium tert-butoxide and 3,5-dichloropyridine and heating indimethylacetamide provides the compound 47. Removal of the chlorine atomof 47 by hydrogenation provides the amine of formula 48, an aspect ofgeneral amine 2.

Amines of general formula 2 can also be prepared by the general routeshown in Scheme 13. Thus, halo pyridine 49 (X is halogen) or halopyrimidine 50 (X is halogen) can be converted to Z6-substituted pyridine51 or Z6-substituted pyrimidine 52, respectively. There are severalmethods through which this can be accomplished, depending on the natureof the Z6. When the Z6 moiety is attached to the Q-containing ringthrough a Z6 nitrogen atom, preferred methods include heating compoundsof formula 49 or 50 with an excess of the amine Z6-H either neat or in asolvent such as N-methylpyrrolidinone, DMF, DMSO or an alcoholic solventat temperatures ranging from RT to 200° C. For the case of aryl andheteroaryl amines Z6-H, additional preferred methods include the heatingof compounds 49 or 50 with an excess of the amine Z6-H and an acidcatalyst (for example, TsOH, HCl, HOAc or the like) in a suitablesolvent such as DMF, DMSO or an alcoholic solvent. Additional preferredmethods for aryl and heteroarylamines Z6-H include combining Z6-H withcompounds 49 or 50 in the presence of a transition metal catalyst suchas a palladium catalyst in a suitable solvent like 1,4-dioxane or DMFwith heating if necessary. When the Z6 moiety is attached to theQ-containing ring through a Z6 oxygen or sulfur atom, preferred methodsinclude heating 49-50 with alcohol or thiol Z6-H in the presence of astrong base (for example, NaH or potassium tert-butoxide) either neatusing Z6-H as the solvent, or in a polar solvent such as DMF or DMSO attemperatures ranging from RT to 200° C. When the Z6 moiety is attachedto the Q-containing ring through a Z6 carbon atom, preferred methodsinclude contacting compounds 49 or 50 with a species of formula Z6-M inthe presence of a palladium catalyst, wherein M is a species thatparticipates in transition-metal catalyzed cross-coupling reactions.Examples of suitable M groups include but are not limited to, boronicacids, boronic esters, zinc, trialkyltin, silicon, magnesium, lithium,and aluminum. Optionally, the transformations shown in Scheme 13 may beperformed with microwave heating. It will be understood by those skilledin the art that the Z6 moieties introduced in Scheme 13 may containoptional protecting groups that will be removed in subsequenttransformations (not shown). Some non-limiting examples of generalScheme 13 are shown in Schemes 14 and 15, below.

In Scheme 14, phenol 33 and 2,4-dichloropyridine (51) are combined usinggeneral Scheme 9 to provide the chloropyridine 52. Further reaction ofchloropyridine with the N-methylpyrazole boronate 53 in the presence ofpalladium tetrakis(triphenylphosphine) provides 54, an example ofgeneral amine 2.

Scheme 15, shows the preparation of amino pyridine 55 fromchloropyridine 52 by the general route of Scheme 13. Preferredconditions for this transformation include the contacting ofchloropyridine 52 with isopropylamine in N-methylpyrrolidinone withmicrowave heating.

Scheme 16 illustrates an alternative preparation of compounds of generalformula 1, represented by the preparation of urea 61. In the instancewhen general amine 2 is primary (R3=H), amine 2 can be converted to anisopropenyl carbamate 56, trichloroethyl carbamate 57, or 4-nitrophenylcarbamate 58 by reaction with isopropenyl chloroformate, trichloroethylchloroformate or 4-nitrophenyl chloroformate, respectively.Alternatively, by analogy to Scheme 2, amine 2 (R3=H) can be convertedto a discrete isocyanate 59. By analogy to Scheme 1, reaction ofcarbamates 56-58 or isocyanate 59 with R3-substituted amine 60 providesurea 61, an example of general formula 1.

An additional subset of ureas of general formula 1 can be prepared asillustrated in Scheme 17. In the instances when R3 is not H, themono-substituted ureas 1 or 61 can be optionally further transformedinto bis-R3-substituted ureas 62 (Formula 1). Thus, in Scheme 17,exposure of 1 or 61 to alkyl halides or cycloalkyl halides in thepresence of a base, for example potassium carbonate, sodium hydride orpotassium tert-butoxide in a suitable solvent such as DMF provides ureas62 wherein the newly incorporated R3 group is alkyl or cycloalkyl.Alternatively, exposure of ureas 1 or 61 to copper(II) acetate andZ3-substituted phenylboronic acids [See: Chan et. al, Tetrahedron Lett.2003, 44, 3863-3865; Chan et. al, Tetrahedron Lett. 1998, 39, 2933-2936;Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013-9016] provides theanalogous bis-R3-substituted ureas wherein the newly incorporated R3 isZ3-substituted phenyl.

General amines A-NH₂ (6) wherein the A-ring is isoxazole can be preparedby the methods described in Scheme 18. Many examples of R2-substitutedaminoisoxazoles 64 and 65 are commercially available. They can also beprepared from common keto nitrile intermediates 63 by condensation withhydroxylamine either under acidic or alkaline conditions as described inthe literature (Takase, et al. Heterocycles, (1991), 32, pp 1153-1158).Bromination of isoxazoles 64 or 65 using standard conditions (see:Sircar, et. al. J. Org. Chem. (1985), 50, pp 5723-7; Carr, et. al. J.Med. Chem. (1977), 20, pp 934-9; Chan et al., U.S. Pat. No. 5,514,691)provides bromo isoxazoles 66 and 67 respectively. By analogy to Schemes7 and 8, 66 and 67 can be converted to A1-containing amino isoxazoles 68and 69, examples of general amine 6 and 25, through palladium-mediatedcouplings with reagents of formula A1-M (70), wherein the “M” moiety ofA1-M is a moiety that participates in transition metal catalyzed crosscoupling reactions, such as a boronic acid or ester, stannane, silane,organozinc or other organometallic moiety known by those skilled in theart to be a suitable substrate for such processes. Using the generalmethods of Schemes 1 and 2, amines 68 and 69 can be converted to ureasof general formula 1. It will be understood by those skilled in the artthat the A1-moiety of 68-70 may contain protecting groups that may beremoved prior to or after conversion to ureas of formula 1 byappropriate de-protection conditions. It will be further understood thatthe amino group of 64-69 may be optionally protected with a suitableprotecting group (such as a tert-butylcarbamate) if desired tofacilitate the bromination or palladium coupling steps.

By analogy to Scheme 18, amines 73 and 74, examples of general aminesA-NH₂ (6) wherein the A-ring is isothiazole, can be prepared as shown inScheme 19 by the reaction of bromo isothiazoles 71 and 72 and A1-M (70).The requisite isothiazoles 71 and 72 are accessible by methods describedin the literature (See; Hegde, V., WO 94/21647 (1994); Hackler, et. al.J. Heterocyclic Chem. (1989), 26, pp 1575-8). Using the general methodsof Schemes 1 and 2, amines 73 and 74 can be converted to ureas ofgeneral formula 1.

2.1 Examples

General Method A: To a stirring solution of carboxylic acid (0.50 mmol,1.00 eq) and DPPA (0.75 mmol, 1.50 eq) in 1,4-dioxane (5.0 ml) at RT wasadded Et₃N (1.5 mmol, 3.00 eq). After stirring for 30 min at RT, theappropriate amine (0.76 mmol, 1.50 eq) in dioxane was added and themixture was heated at 95-100° C. After 2 h, the completed reaction wascooled to RT, diluted with brine and extracted with EtOAc (2×). Thecombined organics were washed with 3M HCl (1×), satd. NaHCO₃ (2×), andbrine (1×), dried (MgSO₄), filtered and evaporated to give the crudeproduct which was purified by flash column chromatography to afford thetarget urea.

Example A1

4-Amino-2-fluorophenol (1.13 g, 8.9 mmol) and Example A22 (1.5 g, 8.9mmol) were combined by the procedure of Example A2 to provide4-(4-amino-2-fluorophenoxy)-N-methylpicolinamide (300 mg, 13% yield).¹H-NMR (DMSO-d₆) δ 8.78 (d, J=4.8 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H), 7.32(d, J=2.4 Hz, 1H), 7.11 (m, 1H), 7.01 (t, J=9.0 Hz, 1H), 6.51 (dd,J=13.2, 2.4 Hz, 1H), 6.42 (dd, J=8.4, 1.6 Hz, 1H), 5.51 (br s, 2H), 2.76(d, J=4.8 Hz, 3H); MS (ESI) m/z: 262.1 (M+H⁺).

Example A2

A solution of 4-amino-3-fluorophenol (2.00 g, 15.7 mmol) in anhydrousDMA (32 mL) was degassed by evacuation of the head space and backfillingwith argon (repeated 3×). The solution was treated with potassiumtert-butoxide (2.12 g, 18.9 mmol) and the resultant mixture wassonicated briefly to bring all solids into the solvent volume and wasstirred at RT for 30 min. Example A22 (2.68 g, 15.7 mmol) was added. Thereaction mixture was degassed a second time and the reaction mixture washeated to 100° C. overnight under argon. The reaction mixture was pouredinto ethyl acetate (400 mL) and washed with water (3×100 mL) andsaturated brine (2×100 mL). The combined aqueous was extracted withEtOAc (100 mL). The combined organics were dried (MgSO₄), concentratedin vacuo to a brown oil and purified by silica gel chromatography toprovide 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (3.18 g, 77%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (m, 1H), 8.48 (d, J=5.7 Hz,1H), 7.36 (d, J=2.6 Hz, 1H), 7.10 (dd, J=5.7, 2.6 Hz, 1H), 7.02 (dd,J=11.8, 2.6 Hz, 1H), 6.86 (t, J=9.8 Hz, 1H), 6.79 (dd, J=8.9, 2.5 Hz,1H), 5.23 (s, 2H), 2.79 (d, J=4.9 Hz, 3H); MS (ESI) m/z: 262.0 (M+H⁺).

Example A3

In NMP (15 mL) was placed 3-amino-4-chlorophenol (1.70 g, 11.8 mmol) andpotassium t-butoxide (1.40 g, 12.4 mmol) and the mixture was stirredovernight at RT. The dark solution was treated with the3,5-difluoropyridine (2.73 g, 23.7 mmol) and powdered potassiumcarbonate (818 mg, 5.92 mmol) and the mixture was then warmed to 80° C.and stirred for 24 h. The resulting black mixture was cooled to RT,diluted with brine (100 mL) and extracted with ethyl acetate (3×50 mL).The combined ethyl acetate extracts were washed with saturated sodiumbicarbonate (50 mL), water (50 mL) and brine (50 mL), dried (Na₂SO₄),concentrated in vacuo and purified via column chromatography to yield2-chloro-5-(5-fluoropyridin-3-yloxy)benzenamine as a thick oil which wasused without further purification. ¹H-NMR (DMSO-d₆): δ 5.57 (br s, 2H),6.26-6.30 (dd, 1H), 6.50 (s, 1H), 7.19-7.22 (m, 1H), 7.45-7.50 (m, 1H),8.26 (s, 1H), 8.39 (s, 1H). MS (ESI) m/z: 239.0 (M+H⁺).

Example A4

A mixture of Example A10 (4.6 g, 19.3 mmol) and 10% Pd(OH)₂/C (0.5 g,0.35 mmol) in EtOH (50 mL) was stirred under a H₂ atmosphere at RT for 3h. The mixture was filtered through Celite® and washed with EtOH. Thefiltrate was concentrated to give 2-fluoro-5-(pyridine-3-yloxy)aniline(3.5 g, 88% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (d, J=2.4 Hz, 1H),8.48 (d, J=3.9 Hz, 1H), 7.80-7.69 (m, 2H), 7.05 (dd, J=11.1, 8.7 Hz,1H), 6.53 (dd, J=7.5, 3.0 Hz, 1H), 6.28 (dt, J=8.7, 3.3 Hz, 1H); MS(ESI) m/z: 205.3 (M+H⁺).

Example A5

To a solution of 2,4-difluorophenol (2 g, 15.4 mmol) in CH₂Cl₂ (20 mL)was added triethyl amine (3.21 ml, 23 mmol) and ethyl chloroformate(1.77 ml, 18.4 mmol) at 0° C. After stirring the mixture for 1 h at RT,sat. NaHCO₃ solution (30 mL) was added, the organic layer was separatedand the aqueous layer was extracted with CH₂Cl₂ (1×25 ml). The combinedorganic layers were washed with brine, dried (Na₂SO₄) and concentratedto afford 2,4-difluorophenyl ethyl carbonate (3.11 g, 100% yield) as aliquid.

To a solution of 2,4-difluorophenyl ethyl carbonate (3.1 g, 16 mmol) insulphuric acid (10 mL) was added fuming HNO₃ (0.78 ml, 19 mmol) slowly,keeping the internal temperature around 0° C. After 15 min ice coldwater (70 mL) was added, the product was extracted with ethyl acetate(2×50 mL), the combined organic layers were washed with brine, dried(Na₂SO₄) and concentrated to afford the nitro product as a thick syrup.This nitro product was dissolved in methanol (20 mL) and to thissolution was added solid NaHCO₃ (4.0 g, 47 mmol) and the resultantmixture was stirred for 16 h at RT. The mixture was filtered and thefiltrate was concentrated. The resulting solid was dissolved in water(20 ml) and acidified with 3M HCl solution to pH˜5. The product wasextracted with CH₂Cl₂ (3×25 mL), the combined organic layers were washedwith brine, dried (Na₂SO₄) and concentrated to afford2,4-difluoro-5-nitrophenol (2.34 g, 84% yield). ¹H NMR (400 MHz,Acetone-d₆) δ 9.59 (s, 1H), 7.78 (t, J=7.2 Hz, 1H), 7.45 (t, J=10.4 Hz,1H); MS (ESI) m/z: 176.0 (M+H⁺).

To a suspension of 2,4-difluoro-5-nitrophenol (1.01 g, 5.77 mmol) inEtOAc was added palladium hydroxide (0.08 g, 0.57 mmol) and theresulting slurry was stirred under a hydrogen atmosphere for 6 h. Themixture was filtered through a Celite® pad, washing with EtOAc (2×10 mL)and the filtrate was concentrated to afford 5-amino-2,4-difluorophenol(0.8 g, 96% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (s, 1H),6.91 (t, J=7.2 Hz, 1H), 6.35 (t, J=8.8 Hz, 1H), 4.84 (brs, 2H); MS (ESI)m/z: 146.0 (M+H⁺).

To a solution of 5-amino-2,4-difluorophenol (0.3 g, 2.07 mmol) in DMSO(2 mL) was added potassium t-butoxide (0.23 g, 2.07 mmol) at RT. Afterstirring for 1 h, 3,5-dichloropyridine (0.37 g, 2.5 mmol) and potassiumcarbonate (0.14 g, 1 mmol) were added and the mixture was heated to 190°C. for 1 h in microwave reactor. Water (30 mL) was added, and theproduct was extracted with EtOAc (2×35 mL) and the combined organiclayers were washed with brine solution, dried (Na₂SO₄), concentrated invacuo and purified by chromatography (EtOAc/hexane) to afford5-(5-chloropyridin-3-yloxy)-2,4-difluorobenzenamine (0.35 g, 66% yield)as a solid. ¹H NMR (400 MHz, Acetone-d₆) δ 8.33-8.30 (m, 2H), 7.44 (t,J=2.4 Hz, 1H), 7.13 (t, J=10.8 Hz, 1H), 6.78 (t, J=8.4 Hz, 1H), 4.85(brs, 2H); MS (ESI) m/z: 257.0 (M+H⁺).

To a solution of 5-(5-chloropyridin-3-yloxy)-2,4-difluorobenzenamine(0.35 g, 1.4 mmol) in 1M HCl solution (10 mL) was added Pd/C (0.015 g)and mixture was shaken on a Parr apparatus under a hydrogen atmosphere(40 psi) for 24 h. The mixture was filtered through Celite® and thefilter pad was washed with water (2×5 mL) and the filtrate wasconcentrated on the lyophilizer to afford the hydrochloride salt. Thiscompound was neutralized with sat aq NaHCO₃ solution, the free amineextracted into EtOAc (2×35 mL) and the combined organic layers werewashed with brine, dried (Na₂SO₄) and concentrated to yield2,4-difluoro-5-(pyridin-3-yloxy)benzenamine (0.19 g, 63% yield) as asolid. ¹H NMR (400 MHz, Acetone-d₆) δ 8.33-8.30 (m, 2H), 7.37-7.29 (m,2H), 7.09 (t, J=10.4 Hz, 1H), 6.70 (t, J=8.4 Hz, 1H), 4.78 (brs, 2H); MS(ESI) m/z: 223.0 (M+H⁺).

Example A6

A solution of 4-amino-o-cresol (0.301 g, 2.44 mmol) in anhydrousdimethylacetamide (6 mL) was de-gassed in vacuo and treated withpotassium tert-butoxide (0.33 g, 2.93 mmol) under argon. The reactionmixture was sonicated briefly to suspend all solid matter in the liquidvolume. The reaction was further stirred at RT for 30 min. Example A22(0.417 g, 2.44 mmol) was added and the resultant mixture was heated to100° C. overnight. The cooled reaction mixture was partitioned betweenethyl acetate (50 mL) and water (20 mL). The organic layer was furtherwashed with water (3×20 mL) and saturated brine (2×20 mL). The combinedaqueous phases were extracted with ethyl acetate (2×20 mL). The combinedorganic phases were dried (MgSO₄), concentrated in vacuo, and purifiedby silica gel chromatography (EtOAc/hexanes) to provide4-(4-amino-2-methylphenoxy)-N-methylpicolinamide (530 mg, 84% yield) asa yellow foam. ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (m, 1H), 8.45 (dd,J=4.6, 0.5 Hz, 1H), 7.27 (dd, J=2.6, 0.4 Hz, 1H), 7.04 (dd, J=5.5, 2.6Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.53 (d, J=2.3 Hz, 1H), 6.48 (dd,J=8.6, 2.5 Hz, 1H), 5.10 (s, 2H), 2.78 (d, J=5.0 Hz, 3H), 1.93 (s, 3H);MS (ESI) m/z: 258.0 (M+H⁺).

Example A7

Using a procedure analogous to Example A2,4-amino-3-fluorophenol (14 g,0.11 mmol) and Example A25 (16g, 0.10 mmol) were combined to provide4-(4-amino-3-fluorophenoxy)picolinamide (8.8 g, 36% yield). ¹H NMR (300MHz, DMSO-d₆) δ 8.46 (d, J=5.7 Hz, 1H), 8.09 (br s, 1H), 7.68 (br s,1H), 7.34 (d, J=2.4 Hz, 1H), 7.10 (dd, J=5.6, 2.6 Hz, 1H), 7.01 (dd,J=5.7, 2.4 Hz, 1H), 6.84 (t, J=9.0 Hz, 1H), 6.77 (dd, J=5.7, 2.4 Hz,1H), 5.22 (s, 2H); MS (ESI) m/z: 248.1 (M+H⁺).

Example A8

A solution of Example A23 (2.0 g, 8.4 mmol) in 2-amino-ethanol (6.0 mL)was heated to 150° C. for 3 h. The solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography to provide2-(4-(4-amino-3-fluorophenoxy)-pyridin-2-ylamino)-ethanol (1.2 g, 54%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.78 (d, J=5.6 Hz, 1H), 6.85 (dd,J=12.0, 2.4 Hz, 1H), 6.78 (t, J=8.8 Hz, 1H), 6.67 (dd, J=8.8, 2.0 Hz,1H), 6.44 (t, J=5.2 Hz, 1H), 6.06 (dd, J=6.0, 2.4 Hz, 1H), 5.80 (d,J=2.0 Hz, 1H), 5.08 (s, 2H), 4.68 (br s, 1H), 3.43 (m, 2H), 3.25-3.20(m, 2H); MS (ESI) m/z: (M+H⁺) 264.1

Example A9

A solution of Example A23 (4.0 g, 16.8 mmol) andN,O-dimethylhydroxylamine HCl (3.3 g, 34 mmol) were combined in1,4-dioxane (50 mL) and the reaction mixture was heated overnight at110° C. The reaction mixture was concentrated in vacuo, neutralized with3M NaOH and extracted with EtOAc (3×). The combined organic phases werewashed with brine, dried (MgSO₄) and concentrated in vacuo to obtain4-(4-amino-3-fluorophenoxy)-N-methoxy-N-methylpyridin-2-amine (4.4 g,99% yield). ¹H NMR (DMSO-d₆) δ 8.06 (d, J=5.2 Hz, 1H), 6.95 (dd, J=12.4,2.8 Hz, 1H), 6.83 (dd, J=8.8, 8.4 Hz, 1H), 6.75 (dd, J=8.4, 2.4 Hz, 1H),6.43 (d, J=2.4 Hz, 1H), 6.37 (dd, J=5.6, 2.4 Hz, 1H), 5.16 (s, 2H), 3.61(s, 3H), 3.14 (s, 3H); MS (ESI) m/z: 264.2 (M+H⁺).

A mixture of2-fluoro-4-(2-(methoxy(methyl)amino)pyridine-4-yloxy)aniline (2.0 g, 7.6mmol) and 10% Pd/C (200 mg, 0.18 mmol) in MeOH (15 mL) was stirred undera H₂ atmosphere (50 psi) at RT for 48 h. The mixture was filteredthrough Celite® and the cake was washed with MeOH. The filtrate wasconcentrated to afford4-(4-amino-3-fluorophenoxy)-N-methylpyridin-2-amine (1.2 g, 68% yield).¹H NMR (DMSO-d₆) δ 7.86 (d, J=6.3 Hz, 1H), 6.82-6.69 (m, 3H), 6.18 (dd,J=6.0, 2.1 Hz, 1H), 5.84 (d, J=2.1 Hz, 1H), 5.41 (br s, 1H), 3.62 (s,2H), 2.84 (d, J=3.0 Hz, 3H); MS (ESI) m/z: 234.2 (M+H⁺).

Example A10

A solution of Example A24 (0.95 g, 7.47 mmol) and potassiumtert-butoxide (0.92 g, 8.2 mmol) in dimethylacetamide (2.0 mL) wasdegassed under vacuum and backfilled with N₂ (4×) and then stirred for30 min. 3,5-Dichloropyridine was added and the resulting solution washeated to 80° C. overnight. The mixture was filtered and the filtratewas concentrated in vacuo and purified by silica gel chromatography toprovide 5-(5-chloropyridin-3-yloxy)-2-fluoroaniline (0.5 g, 28% yield).¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s, 1H), 8.29 (s, 1H), 7.51 (s, 1H),7.00 (dd, J=10.8, 8.8 Hz, 1H), 6.46 (dd, J=7.6, 2.8 Hz, 1H), 6.22 (m,1H), 5.38 (s, 2H); MS (ESI) m/z: 239.2 (M+H⁺).

Example A11

A mixture of Example A8 (0.263 g, 1.0 mmol), imidazole (0.0749 g, 1.1mmol) and TBSCl (0.181 g, 1.2 mmol) in DMF (10 mL) was stirred at RTovernight. Solvent was removed under reduced pressure. The residue wasquenched with H₂O (10 mL) and the pH was adjusted to ˜8 by using NaHCO₃.The aqueous solution was extracted with EtOAc (3×20 mL) and the combinedorganic layers were dried (MgSO₄), concentrated in vacuo and purified bychromatography to afford4-(4-amino-3-fluorophenoxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)pyridin-2-amine(0.252 g, 67% yield) as a light yellow oil. MS (ESI) m/z: 378.3 (M+H⁺).

Example A12

To a solution of Example A17 (7.5 g, 32.5 mmol) in EtOH (60 mL) wasadded 1.0 M aqueous NaOH (10 mL, 100 mmol). The resultant mixture washeated at 85° C. overnight. The majority of ethanol was removed in vacuoand the concentrate was diluted with water (50 mL) and washed with ethylacetate. The aqueous layer was acidified to pH 1-2 by the addition of 3M HCl. The acidic solution was extracted with EtOAc (3×200 mL) and theextracts were washed with brine, dried (MgSO₄) and concentrated in vacuoto give 5-(3-amino-4-fluorophenoxy)picolinic acid (6.2 g, 77%, yield).¹H-NMR (300 MHz, DMSO-d₆) δ 8.40 (d, J=2.7 Hz, 1H), 8.01 (d, J=8.4 Hz,1H), 7.38 (dd, J=8.7, 2.7 Hz, 1H), 7.03 (dd, J=11.4, 8.7 Hz, 1H), 6.50(dd, J=7.5, 3.0 Hz, 1H), 6.26 (m, 1H), 5.39 (br, s, 2H); MS (ESI) m/z:249.1 (M+H⁺).

5-(3-amino-4-fluorophenoxy)picolinic acid (0.14 g, 0.56 mmol) wasdissolved in THF (3 mL) and stirred at 0° C. for 5 min. 1M Borane (3.4mL) solution was added dropwise to the reaction mixture at 0° C. over aperiod of 30 min. The ice bath was removed and stirring continued at RTfor 7 hours. The reaction mixture was cooled in an ice bath and treatedwith 3M HCl (5 mL). The solution was heated for 1 h at 50° C. Thesolution was washed with EtOAc (2×) and the aqueous layer was cooled inan ice bath and neutralized with 3M NaOH. The solution was extractedwith EtOAc (3×), the combined organic layers were washed with brine,dried (Na₂SO₄) and concentrated in vacuo to obtain(5-(3-amino-4-fluorophenoxy)pyridin-2-yl)methanol (0.13 g, 98% yield).¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J=2.8 Hz, 1H), 7.46 (d, J=8.8 Hz,1H), 7.40 (dd, J=2.8, 8.4 Hz, 1H), 6.99 (dd, J=8.8, 11.2 Hz, 1H), 6.40(dd, J=2.8, 7.6 Hz, 1H), 6.15 (dt, J=3.2, 8.8 Hz, 1H), 5.40 (t, J=5.6Hz, 1H), 5.33 (s, 2H), 4.54 (d, J=6.0 Hz, 2H); MS (ESI) m/z: 235.0(M+H⁺).

Example A13

NaH (100 mg, 3.3 mmol) was slowly added to a solution of Example A12(0.50 g, 2.1 mmol) in dry THF (50 mL) at 0° C. After 30 min, CS₂ (0.49g, 6.4 mmol) was added and the reaction mixture was stirred at 0° C. for1 hour. Methyl iodide (2.4 g, 17 mmol) was added at 0° C. and thereaction mixture was allowed to warm to RT overnight. The solvent wasremoved under reduced pressure to obtain the crude product. The crude,O-(5-(3-amino-4-fluorophenoxy)pyridin-2-yl)methyl S-methylcarbonodithioate (0.69 g, 2.1 mmol) was dissolved in toluene (5 mL) andtributyltin hydride (1 mL) and AIBN (50 mg) were added. The reactionmixture was heated under reflux for 3 hours. The solvent was removedunder reduced pressure and the residue was filtered and washed withCH₂Cl₂. The filtrate was evaporated and the residue was purified bysilica gel column chromatography to obtain2-fluoro-5-(6-methylpyridin-3-yloxy)benzenamine (0.26 g, 56% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 8.20 (d, J=2.8 Hz, 1H), 7.30 (dd, J=2.8, and8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.97 (dd, J=8.8, 11.6 Hz, 1H), 6.38(dd, J=3.2, 7.6 Hz, 1H), 6.13 (dt, J=3.2, 8.8 Hz, 1H), 5.31 (s, 1H),2.44 (s, 3H); MS (ESI) m/z: 219.0 (M+H⁺).

Example A14

A solution of 4-amino-3-fluorophenol (0.20 g, 1.6 mmol) in 4 mL ofanhydrous DMA was treated with potassium tert-butoxide (0.24 g, 1.9mmol). The resultant dark-red solution was stirred at RT for 1 hour in acapped vial. 4-Chloro-2-methoxypyridine (0.26 g, 1.6 mmol) was added andthe reaction mixture was heated overnight at 100° C. Water (50 mL) wasadded and the solution was extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with brine, dried (Na₂SO₄),concentrated in vacuo and purified by silica gel column chromatographyto obtain 2-fluoro-4-(2-methoxypyridin-4-yloxy)benzenamine (0.20 g, 58%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (d, J=6.0 Hz, 1H), 6.95 (dd,J=2.8, 12.0 Hz, 1H), 6.82 (dd, J=8.4, 8.8 Hz, 1H), 6.73 (dd, J=2.0, 8.4Hz, 1H), 6.54 (dd, J=2.4, 6.0 Hz, 1H), 6.10 (d, J=2.4 Hz, 1H), 5.17 (s,1H), 3.81 (s, 3H); MS (ESI) m/z: 235.0 (M+H⁺).

Example A15

A teflon capped vial was charged with 4-amino-3-fluorophenol (0.291 g,2.29 mmol) and anhydrous DMF (2.3 mL). The resultant solution wasde-gassed in vacuo and backfilled with argon (3×). The vial was treatedwith sodium tert-butoxide (0.27 g, 2.41 mmol) under argon and quicklycapped. The reaction mixture was stirred at RT for 1 h. After additionof 4-chloropicolinonitrile (0.317 g, 2.29 mmol) and K₂CO₃ (0.174 g, 1.26mmol), the vial was de-gassed again and heated in a 90° C. oil bathovernight. The reaction mixture was diluted with EtOAc (60 mL) andwashed with brine (25 mL). The aqueous phase was back-extracted withEtOAc (50 mL). The combined organic layers were washed with brine (25mL), dried (MgSO₄), concentrated in vacuo and purified by chromatographyto afford 4-(4-amino-3-fluorophenoxy)picolinonitrile (0.162 g, 31%yield) as a colorless oil. ¹H NMR (DMSO-d₆) δ 8.56 (d, J=5.6 Hz, 1H),7.62 (d, J=2.0 Hz, 1H), 7.14 (dd, J=6.0, 2.8 Hz, 1H), 7.03 (dd, J=11.6,2.4 Hz, 1H), 6.88-6.77 (m, 2H), 5.25 (s, 2H); MS (ESI) m/z: 230.0(M+H⁺).

Example A16

A solution of 5-amino-2-chloro-4-fluorophenol (100 mg, 0.619 mmol) indegassed dimethylacetamide (2 mL) was treated with potassium t-butoxide(83 mg, 0.743 mmol) and 5-chloro-2-cyanopyridine (86 mg, 0.619 mmol).The resultant mixture was heated to 80° C. overnight, then cooled to RTand diluted with water (10 mL). The mixture was extracted with EtOAc (30mL). The organic phase was washed with water (3×30 mL) and brine (30 mL)dried (Na₂SO₄) and concentrated in vacuo to provide5-(5-amino-2-chloro-4-fluorophenoxy)picolinonitrile as a dark oil whichwas used without further purification. MS (ESI) m/z: 264.0 (M+H⁺).

Example A17

A solution of 3-amino-4-fluoro-phenol (5.6 g, 44 mmol) indimethylacetamide (60 mL) was degassed in vacuo and was treated withpotassium tert-butoxide (5.3 g, 47 mmol). The resulting solution wasstirred for 30 min. 5-Bromo-pyridine-2-carbonitrile (6.6 g, 36 mmol) wasadded in one-portion and the mixture was heated at 80° C. overnight. Thesolvent was removed in vacuo and the residue was purified by silica gelchromatography to provide 5-(3-amino-4-fluorophenoxy)picolinonitrile(3.5 g, 44% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ 8.47 (d, J=3.0 Hz, 1H),7.98 (d, J=8.4 Hz, 1H), 7.44 (dd, J=8.8, 2.7 Hz, 1H), 7.06 (t, J=9.2 Hz,1H), 6.52 (d, J=7.6 Hz, 1H), 6.28 (m, 1H), 5.44 (br s, 2H); MS (ESI)m/z: 230.0 (M+H⁺).

Example A18

In DMA (10 mL) was placed 3-amino-4-fluorophenol (500 mg, 3.93 mmol),potassium t-butoxide (441 mg, 3.93 mmol) and4-chloro-2-(methylthio)pyrimidine (632 mg, 3.93 mmol). The mixture waswarmed to 50° C. and stirred overnight. The mixture was cooled to RT anddiluted with water (30 mL), extracted with ethyl acetate (2×25 mL) andthe combined organic phases washed with brine, dried (Na₂SO₄) andconcentrated to yield a dark oil. The oil was purified by columnchromatography to yield2-fluoro-5-(2-(methylthio)pyrimidin-4-yloxy)benzenamine (841 mg, 85%yield) as an oil which was used without further purification. MS (ESI)m/z: 252.0 (M+H⁺).

Example A19

A solution of pyridine-3-boronic acid (0.68 g, 5.5 mmol) and2-methyl-5-nitro phenol (0.85 g, 5.5 mmol) in DCM (10 mL) was treatedwith pyridine (1.00 mL, 12.4 mmol), copper acetate (1.5 g, 8.3 mmol) andpowdered 4A molecular sieves (330 mg). The reaction mixture was stirredfor 7 days at RT open to air. The mixture was poured into water (50 mL)and extracted with DCM (2×50 mL). The combined organic phases werewashed with saturated aq NaHCO₃ (25 mL), water (25 mL), satd NH₄Cl (2×25mL) and brine (25 mL), dried (Na₂SO₄), concentrated in vacuo andpurified via chromatography on silica gel to provide3-(2-methyl-5-nitrophenoxy)pyridine (81 mg, 6% yield). ¹H NMR (400 MHz,CDCl₃) δ 8.48 (dd, J=4.6, 1.0 Hz, 1H), 8.43 (d, J=2.4 Hz, 1H), 7.99 (dd,J=8.0, 2.0 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H),7.39-7.30 (m, 2H), 2.42 (s, 3H); MS (ESI) m/z: 231.0 (M+H⁺).

A solution of 3-(2-methyl-5-nitrophenoxy)pyridine (80 mg, 0.35 mmol) and10% Pd/C (50% wet, 165 mg, 0.08 mmol) in methanol (4 mL) was treatedwith formic acid (89%, 1 mL, 35 mmol) and the resultant solution wasstirred at RT. After 1 h, the reaction mixture was filtered throughCelite®, and the filter cake was washed with methanol. The filtrateswere concentrated in vacuo, diluted with 40 mL of a pH 12 aqueoussolution and extracted with ethyl acetate (3×25 mL). The extracts weredried (Na₂SO₄) and concentrated in vacuo to provide4-methyl-3-(pyridin-3-yloxy)benzenamine (58 mg, 83% yield). ¹H NMR (400MHz, CDCl₃) δ 8.36 (m, 2H), 8.32 (dd, J=4.6, 1.4 Hz, 1H), 7.26-7.18 (m,3H), 7.05 (d, J=8.0 Hz, 1H), 6.49 (dd, J=8.8, 2.4 Hz, 1H), 6.29 (d,J=2.4 Hz, 1H), 2.11 (s, 3H); MS (ESI) m/z: 201.0 (M+H⁺).

Example A20

In DMA (8 mL) was placed 3-amino-4-fluorophenol (281 mg, 2.21 mmol),potassium t-butoxide (248 mg, 2.21 mmol) and5-bromo-2-(trifluoromethyl)pyridine (500 mg, 2.21 mmol). The mixture waswarmed to 75° C. overnight, then cooled to RT and diluted with water (75mL). The mixture was extracted with ethyl acetate (2×40 mL) and thecombined organic phases washed with brine (40 mL), dried (Na₂SO₄),concentrated in vacuo and purified by column chromatography to yield2-fluoro-5-(6-(trifluoromethyl)pyridin-3-yloxy)benzenamine (161 mg, 26%yield) as an oil which was used without further purification. MS (ESI)m/z: 273.0 (M+H⁺).

Example A21

In DMF (5 mL) was placed 5-(3-amino-4-fluorophenoxy)picolinic acid fromExample A12 (500 mg, 2.01 mmol), 2.0 M methylamine solution/THF (10 mL,20.1 mmol) and HOBt (324 mg, 2.12 mmol). To this was addedN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (772 mg, 4.03 mmol) and the solution stirred overnight atRT. The solution was treated with an additional equiv ofN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (775 mg) and warmed to 40° C., then cooled to RT andstirred overnight. The solution was diluted with ethyl acetate (30 mL)and washed with water (30 mL), brine (30 mL), dried (Na₂SO₄) andconcentrated in vacuo to yield5-(3-amino-4-fluorophenoxy)-N-methylpicolinamide (530 mg, 101% yield) asa thick oil, which was used without further purification. MS (ESI) m/z:262.0 (M+H⁺).

Example A22

To stirring anhydrous DMF (25 mL) was slowly added SOCl₂ (125 mL) atsuch a rate that the reaction temperature was maintained at 40-50° C.Pyridine-2-carboxylic acid (25 g, 0.2 mol) was added in portions over 30min and the resulting mixture was heated at reflux for 16 h during whichtime a yellow solid precipitated. After cooling to RT, the mixture wasdiluted with toluene (80 mL) and concentrated. This process was repeatedthree times. The resulting dry residue was washed with toluene and driedunder reduced pressure to yield 4-chloro-pyridine-2-carbonyl chloride(27.6 g, 79% yield), which was used in the next step withoutpurification.

To a solution of 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 0.16mol) in anhydrous THF (100 mL) at 0° C. was added dropwise a solution ofMeNH₂ in EtOH. The resulting mixture was stirred at 3° C. for 4 h. Thereaction mixture was concentrated under reduced pressure to yield asolid, which was suspended in EtOAc and filtered. The filtrate waswashed with brine (2×100 mL), dried and concentrated to yield4-chloro-N-methylpicolinamide (16.4 g, 60% yield) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.78 (br s, 1H), 8.55 (d, J=5.2 Hz, 1H), 7.97(d, J=2.0 Hz, 1H), 7.66 (m, 1H), 2.82 (d, J=4.8 Hz, 3H); MS (ESI) m/z:171.0 (M+H⁺).

Example A23

Using a procedure analogous to Example A2, 2,4-dichloropyridine (8.0 g,54 mmol) and 3-fluoro-4-aminophenol (8.0 g, 62.9 mmol) were combined toprovide 4-(2-chloro-pyridin-4-yloxy)-2-fluorophenylamine (11g, 86%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.24 (d, J=5.7 Hz, 1H), 7.00 (dd,J=9.0, 2.7 Hz, 1H), 6.89-6.73 (m, 4H), 5.21 (br s, 2H); MS (ESI) m/z:239.2 (M+H⁺).

Example A24

Methyl chloroformate (77.3 g, 0.82 mol) was added dropwise to a −10° C.solution of 2-chloro-4-fluorophenol (100 g, 0.68 mol) and sodiumhydroxide (32.8 g, 0.82 mol) in water (550 mL). After complete addition,the precipitated solid was collected by filtration and washed with waterto give 2-chloro-4-fluorophenyl methyl carbonate (110 g, 79% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 7.62 (dd, J=8.1, 2.7 Hz, 1H), 7.50 (dd, J=9.0,5.4 Hz, 1H), 7.30 (td, J=8.1, 3.0 Hz, 1H), 3.86 (s, 3H); MS (ESI) m/z:205.2 (M+H⁺).

To a suspension of 2-chloro-4-fluorophenyl methyl carbonate (110 g, 0.54mol) in conc. H₂SO₄ (50 mL) was slowly added a mixture comprised ofconc. H₂SO₄ (40 mL) and fuming HNO₃ (40.8 mL, 0.89 mol). The resultantmixture was stirred for 30 min at 0° C. The reaction mixture was pouredinto ice water and the precipitated solid was collected by filtrationand washed with water to give 2-chloro-4-fluoro-5-nitrophenyl methylcarbonate (120g, 90% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.45 (d, J=7.2Hz, 1H), 8.12 (d, J=10.8 Hz, 1H), 3.89 (s, 3H); MS (ESI) m/z: 250.1(M+H⁺).

A mixture of 2-chloro-4-fluoro-5-nitrophenyl methyl carbonate (120g 0.48mol) and sodium hydroxide (22.7 g, 0.57 mol) in water (300 mL) wasrefluxed for 4 h. The insoluble solids were removed by filtration andthe filtrate was acidified with dilute HCl. The precipitated solid wascollected by filtration and washed with water to give2-chloro-4-fluoro-5-nitrophenol (90g, 98% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 11.18 (s, 1H), 8.10 (d, J=10.4 Hz, 1H), 7.62 (d, J=7.2 Hz,1H); MS (ESI) m/z: 192.1 (M+H⁺)

2-Chloro-4-fluoro-5-nitrophenol (85 g, 0.45 mol) and 10% Pd/C (25 g,0.023 mol) were combined in EtOH and hydrogenated (50 psi) for 12 h. Thereaction mixture was filtered, concentrated in vacuo and purified bysilica gel chromatography to provide 3-amino-4-fluorophenol (40 g 70%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (s, 1H), 6.70 (dd, J=11.2, 8.8Hz, 1H), 6.14 (dd, J=7.8, 2.4 Hz, 1H), 5.84 (m, 1H), 4.92 (s, 2H); MS(ESI) m/z: 128.2 (M+H⁺).

Example A25

4-Chloropicolinamide was prepared using a procedure analogous to ExampleA22 by substituting NH₃ for MeNH₂. ¹H NMR (300 MHz, DMSO-d₆) δ 8.59 (d,J=5.2 Hz, 1H), 8.18 (br s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.79 (br s, 1H),7.72 (dd, J=5.2, 2.0 Hz, 1H); MS (ESI) m/z: 157.0 (M+H⁺).

Example A26

Using a procedure analogous to Example A2, 2-fluoro-4-aminophenol (2.6g, 24 mmol) and 2,4-dichloropyridine (2.88 g, 20 mol) were combined toprovide 4-(2-chloropyridin-4-yloxy)-3-fluoro-phenylamine (3.2 g, 67%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=5.6 Hz, 1H), 6.99 (m,1H), 6.90 (m, 2H), 6.50 (d, J=1.6 Hz, 1H), 6.41 (d, J=10.4 Hz, 1H), 5.51(s, 2H); MS (ESI) m/z: 239.1 (M+H⁺).

A mixture of 4-(2-chloro-pyridin-4-yloxy)-3-fluoro-phenylamine (2.0 g,8.4 mmol) and benzylmethylamine (20 mL) was heated to 200° C. overnightin a steel bomb. The reaction mixture was concentrated in vacuo andpurified by silica gel chromatography to give4-(4-amino-2-fluorophenoxy)-N-benzyl-N-methylpyridin-2-amine (1.0 g, 37%yield). MS (ESI) m/z: 324.2 (M+H⁺).

To a solution of4-(4-amino-2-fluorophenoxy)-N-benzyl-N-methylpyridin-2-amine (1.0 g, 3.1mmol) in MeOH (10 mL) was added 10% Pd/C (0.25 g, 0.23 mmol). Thereaction was stirred under a H₂ atmosphere (50 psi) at 75° C. for 12 h.The reaction mixture was filtered, concentrated under reduced pressureand purified by reverse phase prep-HPLC to provide4-(4-amino-2-fluorophenoxy)-N-methylpyridin-2-amine (560 mg, 78% yield).¹H NMR (400 MHz, DMSO-d₆) δ 7.80 (d, J=5.6 Hz, 1H), 6.90 (t, J=9.0 Hz,1H), 6.40-6.45 (m, 3H), 6.06 (dd, J=8.0, 2.8 Hz, 1H), 5.73 (d, J=2.8 Hz,1H), 5.37 (s, 2H), 2.68 (d, J=4.8 Hz, 3H); MS (ESI) m/z: (M+H⁺): 234.2.

Example A27

Example A23 (0.597 g, 2.5 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.728 g,3.75 mmol), Cs₂CO₃ (3.10 g, 9.5 mmol) and Pd(PPh₃)₄ (0.289 g, 0.25 mmol)were combined in DMF/H₂O (20 mL). The reaction mixture was degassed,blanketed with N₂ and heated at 90° C. overnight. The completed reactionwas diluted with H₂O (5 mL) and extracted with EtOAc (3×50 mL). Thecombined organics were washed with brine (20 mL), dried (MgSO₄),concentrated in vacuo and purified by chromatography to afford4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorobenzenamine (0.56 g, 83%)as a light yellow solid. ¹H NMR (400 Hz, DMSO-d₆) δ 13.01 (s, 1H), 8.38(d, J=5.6 Hz, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.29 (d, J=2.4 Hz, 1H),7.03 (dd, J=11.6, 2.4 Hz, 1H), 6.89 (t, J=8.8 Hz, 1H), 6.84 (m, J=8.4Hz, 1H), 6.60 (m, 1H), 5.20 (s, 2H); MS (ESI) m/z: 271.0 (M+H⁺).

Example A28

A solution of Example A23 (3 g, 12.6 mmol),1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(5.2 g, 25.2 mmol), and Na₂CO₃ (2.7 g, 25.2 mmol) in DME (18 mL) andwater (6 mL) was sparged with nitrogen for 20 min. Pd(PPh₃)₄ (729 mg,0.63 mmol) was added and the resulting mixture was heated to 100° C. for16 h. The solvent was removed under reduced pressure and the crudeproduct was suspended in water and extracted with EtOAc. The organiclayer was washed with brine, dried (Na₂SO₄), concentrated in vacuo andpurified by silica gel chromatography to give2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)aniline (2 g,56% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (d, J=5.7 Hz, 1H), 8.21 (s,1H), 7.92 (s, 1H), 7.12 (s, J=2.4 Hz, 1H), 6.96 (m, 1H), 6.85-6.72 (m,2H), 6.56 (m, 1H), 5.15 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 285.0(M+H⁺)

Example A29

By analogy to Example A2, 4-amino-3-fluorophenol (0.12 g, 0.53 mmol),potassium tert-butoxide (0.080 g, 0.71 mmol) and tert-butyl4-chloropicolinate (159 mg, 0.53 mmol) were combined to providetert-butyl 4-(4-amino-3-fluorophenoxy)picolinate (151 mg, 67% yield). MS(ESI) m/z: 305.0 (M+H⁺).

To a solution of LiAlH₄ (699 mg, 18.4 mmol) in THF (15 mL) was addedtert-butyl 4-(4-amino-3-fluorophenoxy)picolinate (1.4 g, 4.6 mmol) at 0°C. under N₂. The mixture was stirred at 0° C. for 2 h. The reactionmixture was quenched with 10% aq NaOH solution (4 mL), the resultantsuspension was filtered and the filtrate was extracted with EtOAc (3×30mL) to give (4-(4-amino-3-fluorophenoxy)pyridin-2-yl)methanol (700 mg,70% yield). MS (ESI) m/z: 235.1 (M+H⁺).

A solution of (4-(4-amino-3-fluorophenoxy)pyridin-2-yl)methanol (750 mg,3.2 mmol) and Et₃N (821 mg, 8 mmol) in DMF (10 ml) at 0° C. was treatedwith tert-butyldimethylsilyl chloride (624 mg, 4.16 mmol). The resultingsolution was stirred at RT for 4 hours. The solvent was removed in vacuoand the residue was purified by silica gel column chromatography toprovide4-(2-((tert-butyldimethylsilyloxy)methyl)pyridin-4-yloxy)-2-fluorobenzenamine(370 mg, 33% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J=5.6 Hz, 1H),7.02 (s, 1H), 6.67-6.82 (m, 4H), 4.76 (s, 2H), 3.71 (s, 2H), 0.89 (s,9H), 0.07 (s, 6H); MS (ESI) m/z: 349.2 (M+H⁺).

Example A30

Example A23 (1 g, 4.2 mmol) and ethyl(4-methoxy-benzyl)amine (10 mL)were combined and heated to 200° C. for 30 hours. The reaction solutionwas poured into HOAc/water (20%, V/V) and extracted with EtOAc (3×100mL). The combined organics were washed with brine (3×50 mL) andsaturated NaHCO₃ solution (2×100 mL), dried (NaSO₄), concentrated invacuo and purified by silica gel chromatography to give[4-(4-amino-3-fluoro-phenoxy)-pyridin-2-yl]-ethyl-(4-methoxybenzyl)amine(1.2 g, 78% yield). ¹H NMR (400 MHz, DMSO-d₆) δ7.90 (d, J=5.6 Hz, 1H),7.07 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 6.74 (m, 2H), 6.63 (d,J=7.2 Hz, 1H), 6.02 (d, J=4.0 Hz, 1H), 5.90 (s, 1H), 5.09 (s, 2H), 4.53(s, 2H), 3.67 (s, 3H), 3.44 (m, 2H), 1.00 (t, J=6.8, 3H); MS (ESI) m/z:368.2 (M+H⁺).

Trifluoroacetic acid (10 mL) was added to a solution of[4-(4-amino-3-fluoro-phenoxy)-pyridin-2-yl]-ethyl-(4-methoxybenzyl)amine(1.2 g, 3.27 mmol) in CH₂Cl₂ (50 mL) and the resulting solution washeated to 40° C. overnight. The reaction mixture was concentrated underreduced pressure and the residue was treated with HCl (5 mL, 12M, 60mmol) and water (50 mL). The solution was washed with EtOAc (4×50 mL).The aqueous layer was treated with NaHCO₃ until pH=8 and then extractedwith EtOAc (3×50 mL). The combined extracts were washed with brine (3×50mL), dried (NaSO₄) and concentrated in vacuo to give4-(4-amino-3-fluorophenoxy)-N-ethylpyridin-2-amine (0.45 g, 67% yield).¹H NMR (300 MHz, DMSO-d₆) δ7.79 (d, J=5.7, 1H), 6.85 (dd, J=11.7, 2.4Hz, 1H), 6.78 (t, J=8.7 Hz, 1H), 6.67 (dd, J=8.7, 2.4 Hz, 1H), 6.39 (m,1H), 6.05 (dd, J=5.7, 2.1 Hz, 1H), 5.72 (d, J=2.1 Hz, 1H), 5.09 (s, 2H),3.15 (m, 2H), 1.03 (t, J=7.2, 3H); MS (ESI) m/z: 248.2 (M+H⁺).

Example A31

To a solution of Example A23 (0.30 g, 1.3 mmol) in NMP (5 mL) was addedisopropylamine (0.54 mL, 6.3 mmol) and it was heated under microwave at200° C. for 6 hours. Water was added and the solution was extracted withethyl acetate. The organic layer was washed with brine, dried (MgSO₄),concentrated in vacuo and purified by silica gel column chromatography(EtOAc/hexane: EtOAc: MeOH/CH₂Cl₂) to obtain4-(4-amino-3-fluorophenoxy)-N-isopropylpyridin-2-amine (0.16 g, 49%yield). MS (ESI) m/z: 262.2 (M+H⁺).

Example A32

A solution of 3,5-dinitro-benzonitrile (5 g, 25.9 mol),5-chloro-pyridin-3-ol (3.35 g, 25.9 mol) and K₂CO₃ (7.2 g, 52 mol) inDMF (150 mL) was heated at 100° C. overnight. The mixture wasconcentrated in vacuo and the residue was poured into water. The aqueouslayer was extracted with ethyl acetate (3×150 mL) and the combinedorganics were washed with brine, dried (Na₂SO₄), concentrated in vacuoand purified by silica gel chromatography to afford3-(5-chloro-pyridin-3-yloxy)-5-nitro-benzonitrile (3.1 g, 44% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 8.22(s, 1H), 8.19 (s, 1H), 7.87 (s, 1H).

Iron powder (6.3 g, 112 mmol) was added to a mixture of3-(5-chloro-pyridin-3-yloxy)-5-nitro-benzonitrile (3.1 g, 11.2 mol) inacetic acid (100 mL) and the reaction was stirred at RT for 6 h. Water(200 mL) was added and the mixture was neutralized to pH 7 withsaturated Na₂CO₃ solution and was extracted with EtOAc (3×150 mL). Thecombined organics were washed with brine, dried (Na₂SO₄), concentratedin vacuo and purified on silica gel to give3-amino-5-(5-chloropyridin-3-yloxy)benzonitrile (1.92 g, 71% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 8.53 (d, J=1.6 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H),7.80 (t, J=2.4 Hz, 1H), 6.77 (s, 1H), 6.72 (d, J=1.6 Hz, 1H), 6.56 (d,J=2.0 Hz, 1H), 5.92 (s, 2H); MS (ESI) m/z: 246.2 [M+H]⁺.

Example A33

3,5-dinitro-benzonitrile (3 g, 16 mmol), 6-methylpyridin-3-ol (1.7 g, 16mmol), and K₂CO₃ (4.3 g, 31 mmol) were dissolved in DMF and heated to110° C. overnight. The reaction mixture was poured into water and themixture was extracted with EtOAc. The combined organics were washed withbrine, dried (Na₂SO₄), concentrated in vacuo and purified by silica gelchromatography to provide3-(6-methylpyridin-3-yloxy)-5-nitrobenzonitrile (3 g, 76% yield). ¹H NMR(400 MHz, DMSO) δ 8.50 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 8.01 (s,1H), 7.59-7.56 (d, J=10 Hz, 1H), 7.38-7.36 (d, J=8.4 Hz, 1H), 1.98 (s,3H); MS (ESI) m/z: 256.3 [M+H]⁺.

A mixture of 3-(6-methylpyridin-3-yloxy)-5-nitrobenzonitrile (3 g, 0.012mol) and iron powder in acetic acid (200 mL) was stirred at RT for 6 h.H₂O was added and the mixture was adjusted to pH 7 with saturated Na₂CO₃solution. The aqueous layer was extracted with EtOAc, and the combinedorganics were washed with brine, dried (MgSO₄), concentrated in vacuoand purified by silica gel chromatography to afford3-amino-5-(6-methylpyridin-3-yloxy)benzonitrile (2 g, 76% yield). ¹H NMR(400 MHz, DMSO) δ 8.25 (s, 1H), 7.42 (d, J=10 Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 6.62 (s, 1H), 6.51 (s, 1H), 6.38 (s, 1H), 5.78 (s, 2H), 2.49(s, 3H); MS (ESI) m/z: 226.2 [M+H]⁺.

Example A34

3,5-Dinitrobenzonitrile (1.50 g, 7.77 mmol) was added to a slurry ofpyridin-3-ol (739 mg, 7.77 mmol) and potassium carbonate (10.7 g, 77.7mmol) in DMF (15 mL), the mixture was warmed to 60° C. and stirredovernight. After cooling to RT the reaction was diluted with ethylacetate (50 mL) and water (100 mL). The organic phase was separated,washed with saturated sodium bicarbonate (50 mL) and brine (50 mL),dried (Na₂SO₄), concentrated in vacuo and purified by chromatography(Si-40 column, ethyl acetate/hexanes) to give a light yellow solididentified as 3-nitro-5-(pyridin-3-yloxy)benzonitrile (1.31 g, 69%yield). MS (ESI) m/z: 242.0 (M+H⁺).

A solution of 3-nitro-5-(pyridin-3-yloxy)benzonitrile (1.31 g, 9.42mmol) and tin(II) chloride dehydrate (6.13 g, 27.2 mmol) in ethanol (20mL) was warmed to 70° C. for 2 hrs. After cooling to RT, the reactionwas poured onto ice/water (100 mL). The aqueous mixture was made basic(pH˜=8) with sodium hydroxide, diluted with ethyl acetate (50 mL) andfiltered through paper to remove most salts. This solution was extractedwith ethyl acetate (2×75 mL) and the combined organics washed withbrine, dried (Na2SO4) and concentrated in vacuo to give a light yellowsolid identified as 3-amino-5-(pyridin-3-yloxy)benzonitrile (660 mg, 57%yield). MS (ESI) m/z: 212.0 (M+H⁺).

Example A35

Using a procedure analogous to Example A3, 3-amino-4-fluorophenol (491mg, 3.86 mmol) and 4-chloropyrimidin-2-amine (500 mg, 3.86 mmol) werecombined to give 4-(3-amino-4-fluorophenoxy)pyrimidin-2-amine (509 mg,59% yield). MS (ESI) m/z: 221.0 (M+H⁺).

Example A36

A solution of 1,3-difluoro-2-methylbenzene (15 g, 0.12 mol) in H₂SO₄(100 mL) was treated dropwise with HNO₃ (65%, 11.4 g, 0.12 mol) at −10°C. The resultant mixture was stirred for about 30 min. The mixture waspoured into ice-water and extracted with EtOAc (3×200 mL). The combinedorganics were washed with brine, dried (NaSO₄) and concentrated in vacuoto give 1,3-difluoro-2-methyl-4-nitrobenzene (16 g, 78% yield). ¹H NMR(400 MHz, CDCl₃) δ 7.80 (m, 1H), 6.8-7.1 (m, 1H), 2.30 (s, 3H).

1,3-difluoro-2-methyl-4-nitrobenzene (16 g, 0.092 mol), benzyl alcohol(10 g, 0.092 mol) and K₂CO₃ (25.3 g, 0.18 mol) were combined in DMF (250mL) and heated to 100° C. overnight. The mixture was poured into waterand extracted with EtOAc (3×200 mL). The combined organics were washedwith brine, dried (Na₂SO₄), concentrated in vacuo and purified by columnchromatography on silica gel to give1-benzyloxy-3-fluoro-2-methyl-4-nitrobenzene (8 g, 33% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 8.04 (t, J=8.8 Hz, 1H), 7.30-7.46 (m, 5H), 7.08 (d,J=9.2 Hz, 1H), 5.28 (s, 2H), 2.13 (s, 3H).

1-Benzyloxy-3-fluoro-2-methyl-4-nitrobenzene (8 g, 0.031 mol) and 10%Pd—C (1 g) were combined in methanol (100 mL) and the mixture wasstirred under an H₂ atmosphere (1 atm) overnight. The reaction mixturewas filtered and the filtrate was concentrated in vacuo to give4-amino-3-fluoro-2-methylphenol (4.2 g, 96% yield). ¹H NMR (300 MHz,DMSO-d₆) δ 8.61 (s, 1H), 6.42 (t, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H),4.28 (s, 2H), 1.96 (s, 3H); MS (ESI) m/z: 142.1 [M+H]⁺.

Potassium tert-butoxide (3.5 g, 0.031 mol) was added to a solution of4-amino-3-fluoro-2-methylphenol (4.2 g, 0.03 mol) in DMAc and theresultant mixture was stirred for 30 min at RT. To this mixture wasadded a solution of 2,4-dichloropyridine (4.38 g, 0.03 mol) in DMAc andthe mixture was heated at 100° C. overnight. The reaction mixture wasconcentrated in vacuo and the residue was dissolved in ethyl acetate(200 mL) and filtered through silica gel, washing forward with EtOAc.The filtrate was concentrated and purified by silica gel chromatographyto give 4-(2-chloropyridin-4-yloxy)-2-fluoro-3-methylbenzenamine (3.2 g,42% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (d, J=6.0 Hz, 1H), 6.84 (s,1H), 6.81 (dd, J=5.6, 2.4 Hz, 1H), 6.67 (m, 2H), 5.12 (s, 2H), 1.91 (s,3H); MS (ESI) m/z 253.1 [M+H]⁺.

4-(2-Chloropyridin-4-yloxy)-2-fluoro-3-methylbenzenamine (1.0 g, 3.3mmol),1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1g, 4.8 mmol), Na₂CO₃ (0.84 g, 6.6 mmol) and Pd(PPh₃)₄ (0.25 g, 0.2 mmol)were combined in DME (75 mL) and water (25 mL). The mixture was spargedwith nitrogen for 15 min and was heated to reflux overnight. Thereaction mixture was extracted with EtOAc (3×100 mL) and the combinedorganics were washed with brine, concentrated in vacuo and purified bysilica gel chromatography to give2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)aniline(0.74 g, 75% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (d, J=6.0 Hz, 1H),8.18 (s, 1H), 7.90 (s, 1H), 7.07 (s, 1H), 6.63 (m, 2H), 6.45 (dd, J=5.6,2.4 Hz, 1H), 5.06 (s, 2H), 3.82 (s, 3H), 1.95 (s, 3H); MS (ESI) m/z:299.2 [M+H]⁺.

Example A37

A solution of 1,2,3-trifluoro-4-nitro-benzene (30 g, 0.17 mol) andbenzyl alcohol (18.4 g, 0.17 mol) in DMF (300 mL) was treated with K₂CO₃(35 g, 0.25 mol) and the resulting mixture was stirred at RT for 8 h.Water (300 mL) was added, and the mixture was extracted with EtOAc(3×500 mL). The combined organics were washed with brine, dried (MgSO₄),concentrated in vacuo and chromatographed on silica gel to give1-benzyloxy-2,3-difluoro-4-nitrobenzene (16 g, 36% yield). ¹H NMR (400MHz, DMSO-d₆): δ 8.06 (m, 1H), 7.49-7.30 (m, 6H), 5.37 (s, 2H).

A mixture of 1-benzyloxy-2,3-difluoro-4-nitrobenzene (14 g, 52.8 mmol)and Pd/C (10%, 1.4 g) in MeOH (200 mL) was stirred under a hydrogenatmosphere (30 psi) for 2 h. The catalyst was removed by filtration andthe filtrate was concentrated in vacuo to afford4-amino-2,3-difluoro-phenol (7 g, 92% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 9.05 (s, 1H), 6.45 (t, J=8.8 Hz, 1H), 6.34 (t, J=9.2 Hz, 1H), 4.67 (s,2H).

Using a procedure analogous to Example A2, 4-amino-2,3-difluorophenol (6g, 41.4 mmol), potassium tert-butoxide (4.9 g, 43.5 mmol) and2,4-dichoropyridine (6.1 g, 41.4 mmol) were combined to afford4-(2-chloro-pyridin-4-yloxy)-2,3-difluorophenylamine (7 g, 66% yield).¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J=6.0 Hz, 1H), 7.05 (s, 1H), 6.95(m, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 5.60 (s, 2H).

Example A38

A solution of Example A37 (2 g, 7.8 mmol),1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(1.6 g, 7.8 mmol) and Na₂CO₃ (1.65 mg, 15.6 mmol) in DME (12 mL) and H₂O(4 mL) was sparged with nitrogen for 20 min. Pd(PPh₃)₄ (450 mg, 0.4mmol) was added and the resulting mixture was heated to 70° C. undernitrogen for 16 h. The solvent was removed under reduced pressure andthe crude product was suspended in water and extracted with EtOAc (3×10mL). The organic layer was washed with brine, dried (MgSO₄),concentrated in vacuo and purified by column chromatography on silicagel to give2,3-difluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]phenylamine(1.3 g, 55% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J=6.0 Hz, 1H),8.32 (s, 1H), 8.02 (s, 1H), 7.26 (s, 1H), 6.96 (t, J=8.8 Hz, 1H),6.70-6.67 (m, 2H), 5.62 (s, 2H), 3.92 (s, 3H); MS (ESI) m/z:303.2[M+H]⁺.

Example A39

Example A23 (2.0 g, 8.4 mmol) and 4-methoxybenzylamine (50 mL) werecombined in a steel bomb and heated to 160° C. for 3 h. The reactionmixture was concentrated under reduced pressure and purified by reverseprep-HPLC to giveN-(4-methoxybenzyl)-4-(4-amino-3-fluorophenoxy)pyridin-2-amine (1.0 g,35% yield).

A solution ofN-(4-methoxybenzyl)-4-(4-amino-3-fluorophenoxy)pyridin-2-amine (500 mg,1.47 mmol) in CH₂Cl₂ (10 mL) was treated with ammonium cerium(IV)nitrate (1.64 g, 2.99 mmol) and the resultant mixture was stirred at RTovernight. The reaction mixture was washed with water, concentrated invacuo and purified by silica gel chromatography to yield4-(4-amino-3-fluorophenoxy)pyridin-2-amine (250 mg, 77% yield). ¹H NMR(300 MHz, DMSO-d₆) δ 7.73 (d, J=6.0 Hz, 1H), 6.88 (dd, J=9.0, 2.0 Hz,1H), 6.80 (t, J=8.7 Hz, 1H), 6.68 (m, 1H), 6.06 (dd, J=4.5, 1.8 Hz, 1H),5.84 (s, 2H), 5.75 (d, J=1.5 Hz, 1H), 5.08 (s, 2H); MS (ESI) m/z: 220.3(M+H⁺).

Example A40

A solution of 4-amino-2-methyl-phenol (4.25 g, 34.5 mmol) indimethylacetamide (50 mL) was degassed in vacuo and blanketed withargon. Potassium tert-butoxide (5.0 g, 44.6 mmol) was added and thereaction mixture was de-gassed a second time and stirred at RT underargon for 30 min. 2,4-Dichloro-pyridine (4.6 g, 31.3 mmol) was added andthe mixture was heated to 100° C. overnight. The solvent was removedunder reduced pressure and the residue was purified by silica gelchromatography to give 4-(2-chloropyridin-4-yloxy)-3-methylbenzenamine(4.5 g, 56% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (d, J=5.2 Hz, 1H),6.75-6.80 (m, 3H), 6.45-6.50 (m, 2H), 5.15 (s, 2H), 1.92 (s, 3H); MS(ESI) m/z: 235.1 (M+H⁺).

A solution of 4-(2-chloropyridin-4-yloxy)-3-methylbenzenamine (595 mg,2.54 mmol),1-methyl-4-(4,4,5,5-tetramethyl)-[1,3,2]dioxaborolan-2-yl)-4H-pyrazole(790 mg, 3.80 mmol) and Cs₂CO₃ (2.53 g, 7.77 mmol) in 10 mL of DMF (10mL) and water (3 mL) was de-gassed under vacuum and blanketed withnitrogen. Pd(PPh₃)₄ (295 mg, 0.26 mmol) was added and the reactionmixture was heated to 90° C. overnight. The reaction mixture was dilutedwith EtOAc (30 mL) and washed with water (2×10 mL) and brine (2×10 mL).The aqueous portion was extracted with EtOAc (2×15 mL) and the combinedorganics were washed with brine (10 mL), concentrated in vacuo andpurified on silica gel to provide3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine as apale yellow colored foam (627 mg, 88% yield). ¹H NMR (400 MHz, DMSO-d₆):δ 8.27 (d, J=6.0 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J=0.7 Hz, 1H), 7.07 (d,J=2.2 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 6.49 (d, J=2.5 Hz, 1H), 6.46-6.40(m, 2H), 5.02 (s, 2H), 3.84 (s, 3H), 1.94 (s, 3H); MS (ESI) m/z: 281.2(M+H⁺).

Example A41

4-Chloro-2-methylsulfanyl-pyrimidine (1.4 g, 8.8 mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (2.0 g,10.3 mmol), Na₂CO₃ (2.8 g, 26.4) and Pd(PPh₃)₄ (500 mg, 0.43 mmol) werecombined in a solvent comprised of toluene/EtOH/H₂O (4/4/1, 20 mL). Themixture was degassed by applying a vacuum and backfilling the headspacewith argon. The reaction mixture was heated overnight at 100° C. Theinsoluble portion was filtered and the filtrate was concentrated andpurified by silica gel chromatography to provide2-(methylthio)-4-(1H-pyrazol-4-yl)pyrimidine (1.2 g, 71% yield). ¹H NMR(400 MHz, CDCl₃) δ 8.45 (d, J=6.4 Hz, 1H), 8.24 (s, 1H), 7.23 (s, 1H),7.05 (d, J=6.4 Hz, 1H), 2.51 (s, 3H).

To a solution of 2-(methylthio)-4-(1H-pyrazol-4-yl)pyrimidine (200 mg, 1mmol) in dichloromethane (3 mL) and H₂O (1 mL) was added4-methoxybenzylchloride (200 mg, 1.28 mmol) at 0° C. The mixture wasstirred at RT overnight. The organic layer was separated, washed withbrine and concentrated in vacuo to give crude4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine. ¹H NMR(300 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.50, (d, J=5.4 Hz, 1H), 8.16 (s,1H), 7.40 (d, J=5.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz,2H), 5.30 (s, 2H), 3.72 (s, 3H), 2.51 (s, 3H); MS (ESI) m/z: 313 (M+H⁺).

To a solution of4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine (200mg, 0.64 mmol) in dichloromethane was added m-CPBA (220 mg, 1.28 mmol).The reaction was stirred for 2 hour at RT. Water was added, the organiclayer was separated and the aqueous layer was extracted withdichloromethane. The combined organics were washed with brine andconcentrated in vacuo. The residue was combined with3-amino-4-fluorophenol (165 mg, 1.28 mmol) and K₂CO₃ (176 mg, 1.28 mmol)in DMF (5 mL) and the resultant mixture was heated at 90° C. overnight.After filtration and concentration, the residue was purified by silicagel column chromatography to give5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine(210 mg, 84% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (s, 1H), 8.44, (d,J=5.4 Hz, 1H), 8.10 (s, 1H), 7.42 (d, J=5.4 Hz, 1H), 7.25 (d, J=8.4 Hz,2H), 6.98 (t, J=9.6 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 6.52 (dd, J=2.7,8.7 Hz, 1H), 6.28 (m, 1H), 5.30 (br s, 2H), 5.26 (s, 2H), 3.72 (s, 3H);MS (ESI) m/z: 392.2 (M+H⁺).

To a solution of5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine(50 mg, 0.13 mmol) in dichloromethane (3 mL) was added TFA (0.3 mL) at0° C. and the reaction stirred at RT for 12 h. The solvent was removedin vacuo, the residue was washed with ether and treated with saturatedammonia solution. The solid was collected via filtration and dried undervacuum to give5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine (15 mg, 43%yield). ¹H NMR (300 MHz, MeOD) δ 8.44 (d, J=5.1 Hz, 1H), 8.23 (br s,2H), 7.40 (d, J=5.4, 1H), 7.02 (dd, J=10.8, 8.7 Hz, 1H), 6.73 (dd,J=2.7, 7.2 Hz, 1H), 6.50 (m, 1H); MS (ESI) m/z: 272.2 (M+H⁺).

Example A42

Using a procedure analogous to Example A3, 3-amino-4-fluorophenol (0.127g, 1.0 mmol) and 5-bromo-2-nitropyridine (0.203 g, 1.0 mmol) werecombined to afford 2-fluoro-5-(6-nitropyridin-3-yloxy)benzenamine (0.098g, 39% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.36 (d,J=2.8 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 7.56 (dd, J=8.8, 2.8 Hz, 1H),7.07 (m, 1H), 6.53 (dd, J=7.6, 3.2 Hz, 1H), 6.31 (s, 1H), 5.48 (s, 2H);MS (ESI) m/z: 250.0 (M+H⁺).

Example B1

To a stirring solution of benzyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.991 g, 2.52 mmol, 1.00 eq) in THF (10 ml) and H₂O (2.5 ml) was addedNaIO₄ (1.62 g, 7.56 mmol, 3.00 eq). The resulting suspension was stirredat 25° C. for 30 min and then treated with 3M HCl (1.68 ml, 5.04 mmol,2.0 eq). The mixture was stirred for 2.5 h. The supernatant was decantedaway from the solids, rinsing forward with THF. The combined organicphases were washed with brine (2×), dried (MgSO₄) and concentrated invacuo to give crude2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid(0.640 g, 82% yield) as a foam which was used as is in the nextreaction. ¹H NMR (400 MHz, DMSO-d₆) δ 7.68-7.58 (m, 2H), 7.45-7.29 (m,6H), 7.17 (m, 1H), 5.13 (s, 2H), 4.62-4.56 (brm, 2H), 3.65 (brs, 2H),2.86 (t, 2H, J=5.60 Hz); MS (ESI) m/z: 312.0 (M+H⁺).

To a stirring suspension of2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid(0.640 g, 2.06 mmol, 1.00 eq) and 4 ÅMS (0.64 g) in CH₂Cl₂ (20 ml) wasadded pyridine (0.168 ml, 2.06 mmol, 1.00 eq) followed by ethyl3-t-butyl-1H-pyrazole-5-carboxylate (0.404 g, 2.06 mmol, 1.00 eq) andCu(OAc)₂ (0.374 g, 2.06 mmol, 1.00 eq). The resulting blue-green mixturewas stirred at 25° C. After 40 h, the mixture was diluted with H₂O anddecanted away from the molecular sieves. The layers were separated andthe organic phase was washed with H₂O (2×). The combined aqueous phaseswere extracted with CH₂Cl₂ (1×). The combined organic phases were dried(MgSO₄), concentrated in vacuo and purified by flash chromatography(EtOAc/hexanes) to afford benzyl6-(3-t-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.46 g, 48% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.41-7.28 (m, 5H),7.24-7.20 (m, 3H), 6.96 (s, 1H), 5.15 (s, 2H), 4.67 (brm, 2H), 4.17 (q,2H, J=7.2 Hz), 3.66 (brs, 2H), 2.86 (t, 2H, J=6.0 Hz), 1.29 (s, 9H),1.18 (t, 3H, J=7.2 Hz); MS (ESI) m/z: 462.3 (M+H⁺).

To a stirring solution of benzyl6-(3-t-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.160 g, 0.347 mmol) in 1:1:1 THF/EtOH/H₂O (3 ml) at 22° C. was addedLiOH.H₂O (0.0727 g, 1.73 mmol). After 3 h, the completed reaction wasacidified (pH 2-3) with 1M HCl and extracted with EtOAc (3×). Thecombined organic phases were washed with brine (2×), dried (MgSO₄),filtered and evaporated to afford1-(2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-t-butyl-1H-pyrazole-5-carboxylicacid (0.16 g, 106% yield) as an oil which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.41-7.31 (m, 5H), 7.328-7.20(m, 3H), 6.91 (s, 1H), 5.15 (s, 2H), 4.65 (brm, 2H), 3.66 (brs, 2H),2.86 (t, 2H, J=6.0 Hz), 1.29 (s, 9H); MS (ESI) m/z: 434.2 (M+H⁺).

Example B2

Ethyl3-t-butyl-1-(2-(trifluoromethylsulfonyloxy)quinolin-6-yl)-1H-pyrazole-5-carboxylate(see WO 2006/071940A2, 0.380 g, 0.806 mmol), MeNH₂.HCl (0.109 g, 1.61mmol) and Et₃N (0.449 ml, 3.22 mmol) were combined DMF (8 mL) andstirred at RT overnight. Additional portions of MeNH₂.HCl (0.109 g, 1.61mmol) and Et₃N (0.449 ml, 3.22 mmol) were added and the reaction wasstirred an additional 4 h at RT and 3 h at 60° C. The completed reactionwas diluted with brine and extracted with EtOAc. The extracts werewashed with brine, dried (Na₂SO₄), concentrated in vacuo and purified bysilica gel chromatography to provide ethyl3-tert-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazole-5-carboxylate(240 mg, 85% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (d, J=9.2 Hz, 1H),7.68 (d, J=2.8 Hz, 1H), 7.53 (d, J=9.2 Hz, 1H), 7.46 (dd, J=8.8, 2.0 Hz,1H), 7.17 (q, J=4.8 Hz, 1H), 6.98 (s, 1H), 6.80 (d, J=8.8 Hz, 1H), 4.16(q, J=7.2 Hz, 2H), 2.92 (d, J=4.8 Hz, 3H), 1.32 (s, 9H), 1.13 (t, J=7.2Hz, 3H); MS (ESI) m/z: 353.2 (M+H⁺).

LiOH.H₂O (0.143 g, 3.40 mmol) was added to a solution of ethyl3-tert-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazole-5-carboxylate(0.240 g, 0.68 mmol) in a mixture of water/THF/EtOH (1:1:1, 9 mL). Thereaction mixture was stirred overnight at RT, diluted with 3 M HCl andextracted with EtOAc and THF. The combined organics were washed withbrine, dried (MgSO₄) and concentrated under vacuum to obtain3-tert-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazole-5-carboxylicacid (0.22 g, 100% yield). ¹H-NMR (DMSO-d₆) δ 7.90 (d, J=9.2 Hz, 1H),7.66 (d, J=2.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.46 (dd, J=9.2, 2.8 Hz,1H), 7.14 (m, 1H), 6.88 (brs, 1H), 6.79 (d, J=9.2 Hz, 1H), 2.92 (d,J=4.8 Hz, 3H), 1.31 (s, 9H); MS (ESI) m/z: 325.2 (M+H⁺).

Example B3

A solution of triflic anhydride (42.8 g, 0.15 mol) in CH₂Cl₂ (100 mL)was added dropwise to a 0° C. solution of 6-hydroxyquinoline (20.00 g,0.138 mol) and pyridine (23 g, 0.277 mol) in CH₂Cl₂ (500 mL). Thecooling bath was removed and the resulting solution was stirred at RTfor 4 h. The reaction mixture was washed with water (3×300 mL) and theorganic phase was dried (MgSO₄) and concentrated under vacuum to affordcrude quinolin-6-yl trifluoromethanesulfonate (40 g, >100% yield) as anoil. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.00 (d, 1H, J=2.8 Hz), 8.50 (d, 1H,J=8.0 Hz), 8.21 (d, J=2.8 Hz, 1H), 8.18 (d, J=9.2 Hz, 1H), 7.80 (m, 1H),7.64 (m, 1H); MS (ESI) m/z: 277.9 (M+H⁺).

To a suspension of quinolin-6-yl trifluoromethanesulfonate (40 g, 0.14mol), benzophenone hydrazone (35.6 g, 0.18 mol), cesium carbonate (74 g,0.23 mol) and 1,1′-bis(diphenylphosphino)ferrocene (2.5 g, 4.5 mmol) indegassed toluene (1 L) was added palladium acetate (0.013 g, 0.058mmol). The resultant mixture was heated to 90° C. under a nitrogenatmosphere. After 16 h, the mixture was concentrated in vacuo and theresidue was purified via silica gel column chromatography (EtOAc/petether) to provide 1-(diphenylmethylene)-2-(quinolin-6-yl)hydrazine (32g, 68.6% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.58 (t,J=1.8 Hz, 1H), 8.13 (d, J=3.6 Hz, 1H), 7.80 (d, J=3.6 Hz, 1H), 7.61 (d,J=3.9 Hz, 1H), 7.59-7.51 (m, 4H), 7.50 (d, J=3.6 Hz, 2H), 7.33-7.39 (m,6H); MS (ESI) m/z: 324 (M+H⁺).

A solution of 1-(diphenylmethylene)-2-(quinolin-6-yl)hydrazine (32 g, 99mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (26 g, 0.15 mol) in ethanol(500 mL) was treated with conc HCl (80 ml, 12 N, 0.96 mol) and themixture was heated to reflux overnight. The cooled reaction mixture wasconcentrated under vacuum and the residue was washed with Et₂O to removethe diphenylketone. The crude product was dissolved in EtOAc andneutralized (pH 8) with saturated Na₂CO₃ solution. The organic layer wasdried (Na₂SO₄), concentrated in vacuo and purified by silica gelchromatography to give 5-tert-butyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine(23 g, 87% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ 8.86 (m, 1H), 8.39 (d,J=5.7 Hz, 1H), 8.11-8.02 (m, 3H), 7.54 (m, 1H), 5.46 (s, 1H), 5.42 (brs, 2H), 1.23 (s, 9H); MS (ESI) m/z: 267.2 (M+H⁺).

To a cold solution (−10° C.) of5-tert-butyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine (8.00 g, 30 mmol) in100 ml of CH₂Cl₂ was added pyridine (8.0 ml, 99 mmol) and DMAP (100 mg),followed by a solution of trichloroethyl chloroformate (8.9 ml, 42 mmol)in 30 ml of CH₂Cl₂ over a period of 20 minutes. After stirring for 1hour, water (100 ml) was added, stirring continued for 10 more minutesand the organic layer separated. The organic layer was washed withbrine, dried and the dark brown residue obtained after removal of thesolvent crystallized from acetonitrile to furnish 2,2,2-trichloroethyl3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-ylcarbamate as a white solid(8.23 g, 62% yield). ¹H NMR (DMSO-d₆) δ 10.15 (br s, 1H) 8.93 (m, 1H),8.41 (d, J=8 Hz, 1H), 8.11 (m, 2H), 7.90 (dd, J=8, 2 Hz, 1H), 7.60 (dd,J=6.4, 4.2 Hz, 1H), 6.39 (s, 1H), 4.85 (s, 2H), 1.32 (s, 9H); MS (ESI)m/z: 442 (M+H⁺).

Example B4

Quinolin-6-ylboronic acid (0.34 g, 2.0 mmol) was dissolved in CH₂Cl₂ (30mL) and pyridine (1 mL) with MS (activated 4 Å) and stirred at RT for 6hours. Ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (0.39 g, 2.0 mmol)and copper(II) acetate (0.36 g, 2.0 mmol) were added and the reactionwas stirred at RT for 3 days open to air. The reaction mixture wasfiltered through a pad of Celite®, the filtrate was concentrated invacuo and purified by silica gel chromatography to obtain ethyl3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-5-carboxylate (0.21 g, 33%yield). MS (ESI) m/z: 324.0 (M+H⁺).

Lithium hydroxide (62 mg, 2.6 mmol) was added to a solution of ethyl3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-5-carboxylate (0.21 g, 0.65mmol) in dioxane-H₂O-EtOH (1:1:1, 6 mL). The reaction mixture wasstirred overnight at RT. The solution was concentrated and the residuewas dissolved in H₂O (2 mL). 3M HCl was added and the precipitate wascollected by filtration and washed with water. The solid was dried undervacuum to obtain 3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-5-carboxylicacid (0.18 g, 94% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.96 (dd, J=2.0, 4.0 Hz, 1H), 8.47 (dd, J=1.2, 8.4 Hz, 1H), 8.09 (m,1H), 8.06 (s, 1H), 7.82 (dd, J=2.8, 9.2 Hz, 1H), 7.61 (dd, J=4.8, 8.8Hz, 1H), 7.01 (s, 1H), 1.33 (s, 9H); MS (ESI) m/z: 296.0 (M+H⁺).

Example B5

[3-(5-amino-3-t-butyl-pyrazol-1-yl)naphthalen-1-yl]acetic acid ethylester hydrochloride (see WO 2006/071940, 1.60 g, 4.55 mmol) was treatedwith ammonia in methanol (7 M, 13 mL, 91 mmol) and the reaction mixturewas heated in a sealed tube for 6 days. The solvent was removed in vacuoand the residue was chromatographed to provide2-(3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)naphthalen-1-yl)acetamide(610 mg, 41% yield). MS (ESI) m/z: 323.3 (M+H⁺).

To a mixture of saturated sodium bicarbonate (20 mL), ethyl acetate (20mL) and2-(3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)naphthalen-1-yl)acetamide(300 mg, 0.931 mmol) was added Troc-Cl (296 mg, 1.40 mmol). The mixturewas stirred vigorously overnight. The mixture was diluted with ethylacetate (30 mL) and the organic phase was separated, washed with 5%citric acid (30 mL) and brine (30 mL), dried (Na₂SO₄) and concentratedin vacuo to give a solid which was triturated with ethyl acetate andfiltered to provide 2,2,2-trichloroethyl1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-tert-butyl-1H-pyrazol-5-ylcarbamate(241 mg, 52% yield). MS (ESI) m/z: 499.0 (M+H⁺).

Example B6

To a stirring suspension of tert-butyl5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (seeWO 2006/071940A2, 0.250 g, 0.70 mmol) and Troc-Cl (0.10 ml, 0.74 mmol)in EtOAc (7 ml) at RT was added sat'd. NaHCO₃ (2.9 ml, 2.1 mmol). After3 h, the completed reaction was diluted with hexanes (35 ml) andfiltered. The solid was rinsed well with hexanes and dried to affordtent-butyl5-(3-tert-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate(0.36 g, 97% yield). MS (ESI) m/z: 532.0 (M+H⁺).

Example B7

To a stirring solution of t-butyl6-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(see WO 2006/071940A2, 0.075 g, 0.20 mmol) and Troc-Cl (0.028 ml, 0.21mmol) in EtOAc (2 ml) was added sat'd. NaHCO₃ (0.82 ml, 0.61 mmol). Theresulting biphasic solution was stirred at RT overnight. The layers wereseparated and the aqueous phase was extracted with EtOAc (2×). Thecombined organic phases were washed with brine (1×), dried (MgSO₄) andconcentrated in vacuo to give crude t-butyl6-(3-t-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.110 g, 100% yield). ¹H NMR (DMSO-d₆) δ 9.93 (brs, 1H), 7.29-7.24 (m,2H), 6.83-6.80 (m, 1H), 6.27 (s, 1H), 4.85 (s, 2H), 4.52 (brs, 2H),3.57-3.53 (m, 2H), 2.82-2.79 (m, 2H), 1.44 (s, 9H), 1.27 (s, 9H); MS(ESI) m/z: 545.0 (M+H⁺).

Example B8

A solution of tert-butyl5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (seeWO 2006/071940A2, 0.64 g, 1.80 mmol) in EtOAc (6 mL) was treated with 1Maq NaOH (2.7 mL). To the stirring biphasic reaction mixture at 0° C. wasadded isopropenyl chloroformate (0.26 mL) dropwise over 1 min. Thereaction mixture was stirred for 4 h at RT. The reaction was dilutedwith EtOAc (20 ml). The organic layer was washed with H₂O (2×10 ml),brine (10 ml) dried (MgSO₄) and concentrated to afford tert-butyl5-(3-tert-butyl-5-((prop-1-en-2-yloxy)carbonylamino)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate(0.69 g, 87% yield) as a light yellow foam. ¹H NMR (DMSO-d₆) δ 9.77 (s,1H), 8.52 (s, 1H), 8.17 (d, J=9 Hz, 1H), 7.97 (d, J=2 Hz, 1H), 7.74 (dd,J=9, 2 Hz 1H), 6.34 (s, 1H), 4.7 (m, 2H), 1.80 (s, 3H), 1.67 (s, 9H),1.30 (s, 9H); MS (ESI) m/z: 440.2 (M+H⁺).

Example B9

Using a procedure analogous to Example B3,6-(2-(diphenylmethylene)hydrazinyl)quinoline (4.0 g, 12.3 mmol) and4-methyl-3-oxo-pentanenitrile (1.5 g, 13.5 mmol) were combined toprovide to 3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine. (1.1 g, 36%yield). ¹H NMR (400 MHz, CDCl₃) δ 8.93 (dd, J=4.4, 1.6 Hz, 1H),8.21-8.18 (m, 2H), 8.05-8.02 (m, 2H), 7.44 (dd, J=8.4, 4.4 Hz, 1H), 5.56(s, 1H), 3.85 (br s, 2H), 2.97 (m, 1H), 1.31 (d, J=6.8 Hz, 6H); MS (ESI)m/z: 253.2 (M+H⁺).

Using a procedure analogous to Example B33-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine (0.378 g, 1.5 mmol) wasconverted to 2,2,2-trichloroethyl3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-ylcarbamate (0.391 g, 61%yield). MS (ESI) m/z: 427.0 (M+H⁺).

Example B10

Using a procedure analogous to Example B3,6-(2-(diphenylmethylene)hydrazinyl)quinoline (4.0 g, 12.3 mmol) and3-oxo-pentanenitrile (1.3 g, 1.1 eq) were combined to yield5-ethyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine (2.5 g, 85% yield). ¹H NMR(300 MHz, DMSO-d₆) δ 8.87 (dd, J=7.8, 1.8 Hz, 1H), 8.39 (dd, J=8.4, 1.5Hz, 1H), 8.12 (s, 1H), 8.06-8.03 (m, 2H), 7.54 (dd, J=8.4, 1.2 Hz, 1H),5.46 (br s, 2H), 5.40 (s, 1H), 2.49 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5Hz, 3H); MS (ESI) m/z: 239.2 (M+H⁺).

Using a procedure analogous to Example B3,5-ethyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine (0.378 g, 1.5 mmol) wasconverted to 2,2,2-trichloroethyl3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-ylcarbamate (0.287 g, 41% yield)as a white foam. MS (ESI) m/z: 413.0 (M+H⁺).

Example B11

Using a procedure analogous to a procedure analogous to Example B3,6-(2-(diphenylmethylene)hydrazinyl)quinoline (5.0 g, 15.5 mmol) and4,4,4-trifluoro-3-oxo-butyronitrile (2.3 g, 16.8 mmol) were combined toyield 2-quinolin-6-yl-5-trifluoromethyl-2H-pyrazol-3-ylamine (2.3 g, 53%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.95 (dd, J=1.5, 4.2 Hz, 1H), 8.47(d, J=7.2 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H), 8.14 (d, J=9.3 Hz, 1H), 7.97(dd, J=2.4, 9.0 Hz, 1H), 7.60 (dd, J=7.2, 4.2 Hz, 1H), 5.96 (br s, 2H),5.85 (s, 1H); MS (ESI) m/z: 279.2 (M+H⁺).

Using a procedure analogous to Example B3,2-quinolin-6-yl-5-trifluoromethyl-2H-pyrazol-3-ylamine (0.47 g, 1.7mmol) was converted to 2,2,2-trichloroethyl1-(quinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate (0.333 g,43% yield). MS (ESI) m/z: 453.0 (M+H⁺).

Example B12

Using a procedure analogous to Example B3,6-(2-(diphenylmethylene)hydrazinyl)quinoline (5.0 g, 15.5 mmol) and3-cyclopentyl-3-oxopropanenitrile (3.0 g, 1.1 eq) were combined to yield3-cyclopentyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine (2.3 g, 53% yield).¹H NMR (300 MHz, DMSO-d₆) δ 8.87 (m, 1H), 8.38 (dd, J=1.5, 8.4 Hz, 1H),8.10 (s, 1H), 8.04-8.02 (m, 2H), 7.55 (dd, J=4.2, 8.1 Hz, 1H), 5.41 (brs, 2H), 5.38 (s, 1H), 2.90 (m, 1H), 1.85-1.96 (m, 2H), 1.53-1.70 (m,6H); MS (ESI) m/z: 279.3 (M+H⁺).

Using a procedure analogous to Example B3,3-cyclopentyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine (0.418 g, 1.5 mmol)was converted to 2,2,2-trichloroethyl3-cyclopentyl-1-(quinolin-6-yl)-1H-pyrazol-5-ylcarbamate (0.394 g, 58%yield). MS (ESI) m/z: 453.0 (M+H⁺).

Example B13

Using a procedure analogous to Example B3,6-(2-(diphenylmethylene)hydrazinyl)quinoline (4.0 g, 12.3 mmol) and3-cyclobutyl-3-oxo-propionitrile (1.7 g, 1.1 eq) were combined toprovide 5-cyclobutyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine (1.3 g, 40%yield). ¹H NMR (300 MHz, CDCl₃) δ 8.92 (dd, J=4.5, 1.2 Hz, 1H),8.16-8.20 (m, 2H), 8.00-8.04 (m, 2H), 7.43 (dd, J=8.4, 1.2 Hz, 1H), 5.64(s, 1H), 3.83 (br s, 2H), 3.53 (m, 1H), 2.40-2.20 (m, 4H), 2.08-1.92 (m,2H); MS (ESI) m/z: 265.1 (M+H⁺).

Using a procedure analogous to Example B3,5-cyclobutyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine (0.396 g, 1.5 mmol)was converted to 2,2,2-trichloroethyl3-cyclobutyl-1-(quinolin-6-yl)-1H-pyrazol-5-ylcarbamate (0.412 g, 63%yield). MS (ESI) m/z: 439.0 (M+H⁺).

Example B14

A degassed mixture of ethyl 5-chloro-2-iodobenzoate (0.621 g, 2.00mmol), Pd(PPh₃)₄ (0.116 mg, 0.1 mmol), quinolin-6-ylboronic acid (0.381g, 2.2 mmol), K₂CO₃ (0.553 g, 4.0 mmol), dimethoxyethane (20 mL), andwater (5 mL) was heated under reflux overnight. Solvents were removedunder reduced pressure. The residue was diluted with sat'd NH₄Cl (15 mL)and extracted with EtOAc (3×30 mL). The combined organic layers weredried (MgSO₄), concentrated in vacuo and purified by chromatography toafford ethyl 5-chloro-2-(quinolin-6-yl)benzoate (0.244 g, 39% yield) asa colorless oil. MS (ESI) m/z: 312.0 (M+H⁺).

To a stirring solution of ethyl 5-chloro-2-(quinolin-6-yl)benzoate(0.244 g, 0.78 mmol) in 1:1:1 THF/EtOH/H₂O (21 ml) at RT was addedLiOH—H₂O (0.164 g, 3.91 mmol). The resulting reaction mixture wasstirred at RT overnight. Solvent was removed under reduced pressure andthe residue was diluted with H₂O (10 mL). The aqueous solution wasacidified to pH˜4 with 3M HCl and extracted with EtOAc (3×30 mL). Thecombined organic layers were washed with brine (20 mL), dried (MgSO₄)and concentrated to afford 5-chloro-2-(quinolin-6-yl)benzoic acid (0.201g, 91% yield) as a white solid. MS (ESI) m/z: 284.0 (M+H⁺).

To a stirring solution of 5-chloro-2-(quinolin-6-yl)benzoic acid (0.201g, 0.708 mmol) and TEA (0.148 ml, 1.06 mmol) in 1,4-dioxane (10 ml) atRT, was added DPPA (0.191 ml, 0.244 mmol). After stirring for 30 min atRT, 2,2,2-trichloroethanol (0.680 ml, 7.08 mmol) was added and thereaction was stirred with heating at 100° C. for 2 h. The completedreaction was diluted with brine (10 ml) and extracted with EtOAc (3×25ml). The combined organics were washed with 5% citric acid (10 ml),sat'd. NaHCO₃ (10 ml) and brine (10 ml), dried (MgSO₄), concentrated invacuo and purified by chromatography to afford 2,2,2-trichloroethyl5-chloro-2-(quinolin-6-yl)phenylcarbamate (0.25 g, 82% yield) as a whitesolid. MS (ESI) m/z: 431.0 (M+H⁺).

Example B15

2,2,2-Trichloroethyl 4-chloro-2-(quinolin-6-yl)phenylcarbamate wasprepared from ethyl 4-chloro-2-iodobenzoate using a procedure analogousto Example B14. MS (ESI) m/z: 431.0 (M+H⁺).

Example B16

A mixture of 5-nitro-1H-indazole (50 g, 0.31 mol) and 10% Pd/C (5.0 g)in MeOH (400 mL) was heated under H₂ (30 psi) atmosphere overnight.After the mixture was filtered, the filtrate was concentrated to give1H-indazol-5-ylamine as a yellow solid (40 g, 97% yield). ¹H NMR (300MHz, DMSO-d₆) δ 12.50 (br s, 1H), 7.70 (s, 1H), 7.22 (d, J=6.6 Hz, 1H),6.77 (d, J=6.6 Hz, 1H), 6.74 (s, 1H), 4.72 (br s, 1H); MS (ESI) m/z:134.2 (M+H⁺).

To a solution of 1H-indazol-5-ylamine (8.0 g, 60.1 mmol) in concentratedHCl (20 mL, 240 mmol) was added an aqueous solution (50 mL) of NaNO₂(4.2 g, 60.1 mmol) at 0° C. and the resulting mixture was stirred for 1h. A solution of SnCl₂.2H₂O (27 g, 120 mmol) in conc HCl (30 mL) wasthen added at 0° C. The reaction was stirred for an additional 2 h atRT. A solution of 4-methyl-3-oxo-pentanenitrile (8.0 g, 1.1 eq) inethanol (50 mL) was added and the resultant mixture was heated to refluxovernight. The reaction mixture was concentrated under reduced pressureand was purified by silica gel chromatography to provide2-(1H-indazol-5-yl)-5-isopropyl-2H-pyrazol-3-ylamine (8.5 g, 59% yield,two steps). ¹H NMR (300 MHz, DMSO-d₆) 8.09 (s, 1H), 7.82 (s, 1H), 7.57(d, J=6.6 Hz, 1H), 7.51 (d, J=6.6 Hz, 1H), 5.31 (s, 1H), 5.12 (s, 2H),2.74 (m, 1H), 1.15 (d, J=5.1 Hz, 6H); MS (ESI) m/z: 242.3 (M+H⁺).

A stirring solution of2-(1H-indazol-5-yl)-5-isopropyl-2H-pyrazol-3-ylamine (8.0 g, 33 mmol) indioxane (80 mL)/10% NaOH (30 mL) was treated with (Boc)₂O (8.6 g, 39.4mmol). The resultant mixture was stirred for 3 h and was then extractedwith DCM (3×100 mL). The organic layer was concentrated in vacuo and theresidue was purified by silica gel chromatography to give5-(5-amino-3-isopropyl-pyrazol-1-yl)-indazole-1-carboxylic acidtert-butyl ester (6.8 g, 47%) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.43 (s, 1H), 8.10 (d, J=9.3 Hz, 1H), 8.00 (br s, 1H), 7.82(d, J=9.3 Hz, 1H), 5.36 (s, 1H), 5.29 (br s, 2H), 2.76 (m, 1H), 1.64 (s,9H), 1.16 (d, J=7.2 Hz, 6H). MS (ESI) m/z: 442.2 (M+H⁺).

A solution of tent-butyl5-(5-amino-3-isopropyl-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (1.50g) in EtOAc (15 mL) was treated with 1M aq NaOH (6.8 mL). To the stirredbiphasic reaction mixture at 0° C. was added isopropenyl chloroformate(0.64 mL) drop-wise over 1 min. The reaction mixture was stirred at RTovernight. The reaction mixture was diluted with EtOAc (100 mL), washedwith H₂O (2×30 mL), brine (30 mL), dried (MgSO₄) and concentrated toafford tert-butyl5-(3-isopropyl-5-((prop-1-en-2-yloxy)carbonylamino)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate(1.90 g, 99% yield) as a white foam. MS (ESI) m/z: 425.8 (M+H⁺).

Example B17

Using a procedure analogous to Example B16, 1H-indazol-5-ylamine (5.0 g,37.5 mmol) and 3-oxo-pentanenitrile (4.0 g, 1.1 eq) were combined andpurified by silica gel chromatography to give5-ethyl-2-(1H-indazol-5-yl)-2H-pyrazol-3-ylamine (5.2 g, 61% yield, twosteps). ¹H NMR (300 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.58 (s, 1H), 7.57 (d,J=6.6 Hz, 1H), 7.50 (d, J=6.6 Hz, 1H), 5.30 (s, 1H), 5.13 (br s, 2H),2.47 (q, J=6.9 Hz, 2H), 1.14 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 228.3(M+H⁺).

Using a procedure analogous to Example B16,5-ethyl-2-(1H-indazol-5-yl)-2H-pyrazol-3-ylamine (5.0 g, 22 mmol) wasconverted to 5-(5-amino-3-ethyl-pyrazol-1-yl)-indazole-1-carboxylic acidtert-butyl ester (3.0 g, 42% yield) as a white solid. ¹H NMR (300 MHz,DMSO-d₆): δ 8.42 (s, 1H), 8.09 (d, J=6.6 Hz, 1H), 7.98 (s, 1H), 7.81 (d,J=6.6 Hz, 1H), 5.35 (s, 1H), 5.29 (br s, 2H), 2.44

tert-Butyl 5-(5-amino-3-ethyl-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate(0.50 g) was converted to tert-butyl5-(3-ethyl-5-((prop-1-en-2-yloxy)carbonylamino)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate(0.55 g, 88% yield) using a procedure analogous to Example 16. MS (ESI)m/z: 412.3 (M+H⁺).

Example B18

A solution of N-benzhydrylidene-N′-quinolin-6-yl-hydrazine (32 g, 0.099mol) in EtOH (500 mL) was treated with conc. HCl (80 ml, 0.96 mmol).After stirring for 10 min, 5,5-dimethyl-2,4-dioxo-hexanoic acid ethylester (26 g, 0.15 mol) was added, and the mixture was heated to 80° C.overnight. The reaction was concentrated in vacuo to give a residuewhich was washed with Et₂O to afford ethyl5-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-3-carboxylate hydrochloride(40 g, 0.11 mol, 112% yield). MS (ESI) m/z: 324.1 (M+H⁺).

A suspension of ethyl5-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-3-carboxylate hydrochloride(32 g, 0.089 mol) in THF (300 mL) was treated with aqueous LiOH (2 N,100 mL, 0.20 mmol) and the resultant mixture was heated to 40° C. for 3hours. The reaction was concentrated under reduced pressure and theremaining aqueous layer was washed with EtOAc. The aqueous phase wasacidified to pH 3 and the resultant precipitate was collected byfiltration, washed with cold ether and dried in vacuo to provide5-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-3-carboxylic acid (21 g, 71%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ 9.03 (m, 1H), 8.50 (d, J=8.7 Hz,1H), 8.20 (d, J=2.4 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.7 Hz,2.4 Hz, 1H), 7.67 (dd, J=8.4, 4.4 Hz, 1H), 6.68 (s, 1H), 1.17 (s, 9H);MS (ESI) m/z: 296.3 (M+H⁺).

Example B19

A solution of sodium nitrite (502 mg, 7.27 mmol) in H₂O (8 ml) was addeddropwise to a well-stirred 0° C. mixture of 2-methylquinolin-6-amine(1.00 g, 6.32 mmol) in conc. HCl (10 ml). The resulting mixture wasstirred at 0° C. for 1 h. Tin(II) chloride dihydrate (6.13 g, 27.2 mmol)in conc. HCl (8 ml) was added and stirring was continued at 0° C. for 1h and then RT for 2 h. Ethanol (60 ml) and4,4-dimethyl-3-oxopentanenitrile (1.03 g, 8.22 mmol) were added and themixture was heated at reflux overnight. The completed reaction mixturewas concentrated in vacuo and diluted with ethyl acetate (100 mL). Themixture was cooled in an ice/water bath and made basic (pH˜8) with solidsodium hydroxide. The solution was filtered through Celite, and thefilter cake was washed with water (50 mL) and ethyl acetate (100 mL).The organic phase was separated, washed with brine, dried (Na₂SO₄), andconcentrated to yield a foam. The foam was stirred in ether (50 mL) andallowed to stand for several hours. The resultant solid was collected byfiltration and dried in vacuo to yield3-tert-butyl-1-(2-methylquinolin-6-yl)-1H-pyrazol-5-amine (428 mg, 24%yield). MS (ESI) m/z: 281.2 (M+H⁺).

A solution of 3-tert-butyl-1-(2-methylquinolin-6-yl)-1H-pyrazol-5-amine(420 mg, 1.50 mmol) in CH₂Cl₂ (15 mL) was treated with pyridine (592 mg,7.49 mmol) and TROC-Cl (333 mg, 1.57 mmol). The mixture was stirred atRT for 16 h, then washed with 5% citric acid (2×20 mL), saturated aqNaHCO₃ (20 mL) and brine (20 mL). The organic phase was dried (Na₂SO₄)and concentrated to provide a mixture of 2,2,2-trichloroethyl3-tert-butyl-1-(2-methylquinolin-6-yl)-1H-pyrazol-5-ylcarbamate (73%yield) contaminated with 16% of the bis-Troc aduct. The mixture was usedwithout further purification. MS (ESI) m/z: 456.5 (M+H⁺).

Example B20

Using a procedure analogous to Example B4,imidazo[1,2-a]pyridin-6-ylboronic acid (0.200 g, 1.23 mmol) and ethyl3-tert-butyl-1H-pyrazole-5-carboxylate (0.267 g, 1.36 mmol) werecombined to afford ethyl3-tert-butyl-1-(H-imidazo[1,2-a]pyridin-6-yl)-1H-pyrazole-5-carboxylate(0.0355 g, 9% yield) as a colorless oil. MS (ESI) m/z: 313.2 (M+H⁺).

Using a procedure analogous to Example B4, ethyl3-tert-butyl-1-(H-imidazo[1,2-a]pyridin-6-yl)-1H-pyrazole-5-carboxylate(0.071 g, 0.23 mmol) was converted to3-tert-butyl-1-(H-imidazo[1,2-a]pyridin-6-yl)-1H-pyrazole-5-carboxylicacid (0.0643 g, 99% yield) as a white solid. MS (ESI) m/z: 285.0 (M+H⁺).

Example B21

Using a procedure analogous to Example B4,imidazo[1,2-a]pyridin-6-ylboronic acid (0.500 g, 3.09 mmol) and ethyl3-isopropyl-1H-pyrazole-5-carboxylate (0.619 g, 3.40 mmol) were combinedto afford ethyl3-isopropyl-1-(H-imidazo[1,2-a]pyridin-6-yl)-1H-pyrazole-5-carboxylate(0.098 g, 11% yield) as a colorless oil. MS (ESI) m/z: 299.3 (M+H⁺).

Using a procedure analogous to Example B4, ethyl3-isopropyl-1-(H-imidazo[1,2-a]pyridin-6-yl)-1H-pyrazole-5-carboxylate(0.098 g, 0.33 mmol) was converted to3-isopropyl-1-(H-imidazo[1,2-a]pyridin-6-yl)-1H-pyrazole-5-carboxylicacid (0.087 g, 98% yield) as a white solid. MS (ESI) m/z: 271.0 (M+H⁺).

Example B22

To a stirring suspension of 6-aminobenzothiazole (0.500 g, 3.33 mmol) inconc. HCl (5 ml) at 0-5° C. was added a solution of NaNO₂ (0.276 g, 3.99mmol) in H₂O (5 ml). The mixture was stirred at 0-5° C. for 75 min untila clear yellow solution was obtained. To this was then added a solutionof SnCl₂.2H₂O (2.76 g, 13.3 mmol) in conc. HCl (5 ml). After completingthe addition, the suspension was stirred at RT for 2 h.4-Methyl-3-oxopentanenitrile (0.444 g, 3.99 mmol) and EtOH (50 ml) wereadded and the reaction was stirred with heating at 75° C. After 18 h,the completed reaction was cooled to RT and concentrated to an aqueousresidue. This was chilled thoroughly in ice and made strongly basic (pH12-13) by the addition of 6M NaOH. While still cold the mixture wasextracted with EtOAc (2×). The combined organics were washed with H₂O(2×), brine (1×), dried (MgSO₄), filtered and evaporated to afford crude1-(benzo[d]thiazol-6-yl)-3-isopropyl-1H-pyrazol-5-amine (0.8 g, 93%yield) as an oil which was used as is in the next reaction. ¹H NMR (400MHz, DMSO-d₆) δ 9.36 (s, 1H), 8.30 (d, J=2.4 Hz, 1H); 8.10 (d, J=8.8 Hz,1H), 7.74 (dd, J=2.4 and 8.8 Hz, 1H), 5.36 (s, 1H), 5.33 (brs, 2H), 2.76(septet, J=6.8 Hz, 1H), 1.17 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 259.0(M+H⁺).

To a stirring solution of1-(benzo[d]thiazol-6-yl)-3-isopropyl-1H-pyrazol-5-amine (0.80 g, 3.1mmol) and pyridine (0.51 ml, 6.2 mmol) in CH₂Cl₂ (30 ml) at RT was addedTroc-Cl (0.51 ml, 3.7 mmol). After 2 h, the completed reaction waswashed with 10% CuSO₄ (2×), H₂O (1×), brine (1×), dried (MgSO₄),evaporated and purified by flash column chromatography (EtOAc/hexanes)to afford 2,2,2-trichloroethyl1-(benzo[d]thiazol-6-yl)-3-isopropyl-1H-pyrazol-5-ylcarbamate (0.31 g,23% yield) as an oil. MS (ESI) m/z: 433.0 (M+H⁺), 435.0 (M+2+H⁺).

Example B23

1-Methyl-5-nitro-1H-benzo[d]imidazole (prepared as described in WO2005/092899; 1.14 g, 6.43 mmol) in EtOH (50 ml) was stirred under H₂ (1atm) at RT in the presence of 10% Pd/C (50 wt % H₂O, 1.37 g, 0.643mmol). After 18 h, the completed reaction was filtered on Celite,rinsing forward with EtOH. The combined filtrates were concentrated toafford crude 1-methyl-1H-benzo[d]imidazol-5-amine (1.02 g, 108% yield)as a dark orange oil which was used as is in the next reaction. ¹H NMR(400 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.75 (d,J=2.0 Hz, 1H), 6.59 (dd, J=2.0 and 8.4 Hz, 1H), 4.73 (brs, 2H), 3.69 (s,3H); MS (ESI) m/z: 148.0 (M+H⁺).

Using a procedure analogous to Example B22,1-methyl-1H-benzo[d]imidazol-5-amine (0.50 g, 3.4 mmol), NaNO₂ (0.28 g,4.1 mmol), SnCl₂.2H₂O (2.8 g, 14 mmol) and 4-methyl-3-oxopentanenitrile(0.45 g, 4.1 mmol) were combined to afford crude3-isopropyl-1-(1-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-5-amine(0.63 g, 73% yield) as a foam which was used as is in the next reaction.¹H NMR (400 MHz, DMSO-d₆): δ 8.22 (s, 1H), 7.72 (dd, J=0.40 and 1.2 Hz,1H), 7.60 (dd, J=0.40 and 8.4 Hz, 1H), 7.42 (dd, J=2.0 and 8.4 Hz, 1H),5.32 (s, 1H), 5.08 (brs, 2H), 3.85 (s, 3H), 2.75 (septet, J=6.8 Hz, 1H),1.16 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 250.0 (M+H⁺).

Using a procedure analogous to Example B22,3-isopropyl-1-(1-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-5-amine(0.63 g, 2.5 mmol) was converted to 2,2,2-trichloroethyl3-isopropyl-1-(1-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-5-ylcarbamate(0.5 g, 47% yield) and isolated as an oil. ¹H NMR (400 MHz, DMSO-d₆) δ9.86 (brs, 1H), 8.24 (s, 1H), 7.67 (brs, 1H), 7.62 (d, J=8.4 Hz, 1H),7.36 (dd, J=2.0 and 8.4 Hz, 1H), 6.23 (s, 1H), 4.81 (s, 2H), 3.85 (s,3H), 2.90 (septet, J=6.8 Hz, 1H), 1.22 (d, J=6.8 Hz, 6H); MS (ESI) m/z:430.0 (M+H⁺), 432.0 (M+2+H⁺).

Example B24

To a stirring solution of1-(2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-tert-butyl-1H-pyrazole-5-carboxylicacid from Example B1 (0.320 g, 0.738 mmol, 1.0 eq) and TEA (0.118 ml,0.849 mmol, 1.15 eq) in 1,4-dioxane (7.5 ml) at 20° C. was added DPPA(0.183 ml, 0.849 mmol, 1.15 eq). After 30 min, 2,2,2-trichloroethanol(1.0 ml, 10.4 mmol, 14 eq) was added and the reaction was stirred withheating at 100° C. After 4 h, the completed reaction was diluted withbrine and extracted with EtOAc (2×). The combined organics were washedwith 5% citric acid (1×), satd. NaHCO₃ (1×) and brine (1×), dried(MgSO₄), concentrated in vacuo and purified by silica gel chromatographyto afford benzyl6-(3-tert-butyl-5-((2,2,2-trichloroethoxy)carbonyl)amino-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.260 g, 61% yield) as an oil. MS (ESI) m/z: 579.0 (M+H⁺), 581.0(M+2+H⁺).

Example B25

Using the procedure of Example B26,3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine from Example B9 (1.00g, 4.0 mmol), lithium bis(trimethylsilyl)amide (1.0 M in THF, 7.9 mL,7.9 mmol) and isopropenyl chloroformate (0.48 mL, 4.4 mmol) werecombined to provide prop-1-en-2-yl3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-ylcarbamate (0.85 g, 65%yield). MS (ESI) m/z: 337.2 (M+H⁺).

Example B26

A solution of 5-tert-butyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine fromExample B3 (1.00 g, 3.8 mmol) in THF (20 mL) was cooled to −78° C. andtreated with lithium bis(trimethylsilyl)amide (1.0 M in THF, 7.5 mL, 7.5mmol). The resultant mixture was stirred at −78° C. for 30 min.Isopropenyl chloroformate (0.45 mL, 0.41 mmol) was added and stirringwas continued at −78° C. for 30 min. The reaction mixture was quenchedat −78° C. with aq HCl (2 N, 4 mL, 8 mmol), was warmed to RT andpartitioned between water (200 mL) and EtOAc (200 mL). The organic layerwas separated, washed with brine, dried (MgSO₄), concentrated in vacuoand purified by silica gel chromatography to provide prop-1-en-2-yl3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-ylcarbamate (0.5 g, 38%yield). MS (ESI) m/z: 351.2 (M+H⁺).

Example B27

4-Fluoro-3-nitrophenylboronic acid (0.9 g, 4.9 mmol) was dissolved inCH₂Cl₂ (10 mL) and pyridine (1 mL) with MS (activated 4A) and dried for6 hours. A mixture of 4-fluoro-3-nitrophenylboronic acid, tert-butyl3-isopropyl-1H-pyrazole-5-carboxylate (1.0 g, 4.9 mmol), copper(II)acetate (0.88 g, 4.9 mmol) and molecular sieves (4A activated, powder)was stirred at RT for 7 days open to the air. The reaction mixture wasfiltered through a pad of Celite. The filtrate was concentrated in vacuoand purified by silica gel column chromatography (EtOAc/hexane) toobtain tert-butyl1-(4-fluoro-3-nitrophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.74g, 44% yield). MS (ESI) m/z: 350.3 (M+H⁺).

To a solution of tert-butyl1-(4-fluoro-3-nitrophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.74g, 2.1 mmol) in THF/water (12 mL) was added LiOH (300 mg, 13 mmol) andH₂O₂ (30% wt, 0.96 mL). The reaction mixture was heated overnight at 60°C. Na₂S₂O₃ solution was added until the peroxide test (starch-iodidepaper) was negative. Acetic acid was added until the pH was 4-5. Thesolution was extracted with EtOAc and the organic layer was washed withbrine, dried (MgSO₄), concentrated in vacuo and purified by silica gelcolumn chromatography (EtOAc/hexanes) to obtain tert-butyl1-(4-hydroxy-3-nitrophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.27g, 37% yield). MS (ESI) m/z: 348.3 (M+H⁺).

To a solution of tert-butyl1-(4-hydroxy-3-nitrophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.27g, 0.78 mmol) in ethyl acetate/methanol (1:1, 10 mL) was added palladiumon carbon (30 mg) and the mixture was hydrogenated (50 psi) overnightunder Parr. The solution was filtered and washed with methanol. Thecombined filtrate was concentrated to afford tert-butyl1-(3-amino-4-hydroxyphenyl)-3-isopropyl-1H-pyrazole-5-carboxylate. Thecrude tert-butyl1-(3-amino-4-hydroxyphenyl)-3-isopropyl-1H-pyrazole-5-carboxylate wastreated with 25% TFA in CH₂Cl₂ (2 mL) and stirred overnight at RT. Thesolvent was evaporated to obtain1-(benzo[d]oxazol-5-yl)-3-tert-butyl-1H-pyrazole-5-carboxylic acid. To asolution of1-(benzo[d]oxazol-5-yl)-3-tert-butyl-1H-pyrazole-5-carboxylic acid inxylenes (3 mL) was added triethyl orthoformate (0.16 mL, 0.96 mmol) anda catalytic amount of PPTS. The reaction mixture was heated at 140° C.for 4 hours. The solvent was evaporated and the residue was treated withmethylene chloride with stirring for 1 hour. The resulting solid wasfiltered and washed with methylene chloride to obtain1-(benzo[d]oxazol-5-yl)-3-isopropyl-1H-pyrazole-5-carboxylic acid (0.1g, 45% yield: for three steps). MS (ESI) m/z: 272.0 (M+H⁺).

Example B28

In toluene (8 mL) was placed 1-(diphenylmethylene)hydrazine (1.00 g,5.10 mmol), palladium acetate (10.4 mg, 0.0464 mmol) and2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene(44 mg, 0.0696 mmol) and the reaction was stirred at 100° C. under Arfor 5 min and then cooled to RT. To this dark purple solution was added6-bromoquinoxaline (970 mg, 4.64 mmol), sodium t-butoxide (624 mg, 6.50mmol) and toluene (2 mL). The reaction was placed under Ar and warmed to100° C. for 5 hrs, cooled to RT and stirred overnight. The reaction wasdiluted with ether (50 mL) and water (30 mL) and filtered through aCelite pad. The pad was washed with ether (20 mL) and water (20 mL). Thecombined organic layers were washed with brine (50 mL), dried (Na₂SO₄),concentrated in vacuo and purified by chromatography (ethylacetate/hexanes) to give1-(diphenylmethylene)-2-(quinoxalin-6-yl)hydrazine (305 mg, 20% yield)as a bright yellow foam. ¹H NMR (300 MHz, DMSO-d₆) δ 7.35-7.41 (m, 5H),7.51-7.53 (m, 2H), 7.58-7.65 (m, 3H), 7.75 (s, 1H), 7.89 (s, 2H), 8.61(s, 1H), 8.74 (s, 1H), 9.60 (s, 1H); MS (ESI) m/z: 325.0 (M+H⁺).

In ethanol (10 mL) was placed1-(diphenylmethylene)-2-(quinoxalin-6-yl)hydrazine (300 mg, 0.925 mmol),pivaloylacetonitrile (156 mg, 1.25 mmol) and p-toluenesulfonic acidhydrate (704 mg, 3.70 mmol). The reaction was brought to reflux andstirred overnight. The reaction was cooled to RT, diluted with ethylacetate (50 mL) and saturated sodium bicarbonate (50 mL). The organicphase was separated, washed with 1N NaOH (30 mL) and brine (30 mL),dried (Na₂SO₄), concentrated in vacuo and purified by chromatography(Si-25 column, ethyl acetate/hexanes) to give a tan foam, identified as3-tert-butyl-1-(quinoxalin-6-yl)-1H-pyrazol-5-amine (57 mg, 23% yield).MS (ESI) m/z: 268.2 (M+H⁺).

Example B29

To a solution of phenethylamine (60.5 g, 0.5 mol) and Na₂CO₃ (63.6 g,0.6 mol) in EtOAc/H 0 (800 mL, 4:1) was added ethyl chloroformate,dropwise, (65.1 g, 0.6 mol) at 0° C. during a period of 1 h. The mixturewas warmed to RT and stirred for an additional 1 h. The organic phasewas separated and the aqueous layer was extracted with EtOAc. Thecombined organic phases were washed with H₂O and brine, dried (Na₂SO₄),concentrated in vacuo and purified by flash chromatography to affordethyl phenethylcarbamate (90.2 g). ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.18(m, 5H), 4.73 (brs, 1H), 4.14-4.08 (q, J=6.8 Hz, 2H), 3.44-3.43 (m, 2H),2.83-2.79 (t, J=6.8 Hz, 2H), 1.26-1.21 (t, J=6.8 Hz, 3H).

A suspension of ethyl phenethylcarbamate (77.2 g, 40 mmol) inpolyphosphoric acid (300 mL) was heated to 140-160° C. and stirred for2.5 h. The reaction mixture was cooled to RT, carefully poured intoice-H₂O and stirred for 1 h. The aqueous solution was extracted withEtOAc (3×300 mL). The combined organic phases were washed with H₂O, 5%K₂CO₃ and brine, dried (Na₂SO₄), concentrated in vacuo and purified byflash chromatography to afford 3,4-dihydro-2H-isoquinolin-1-one (24 g).¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (brs, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.43(t, J=7.5 Hz, 1H), 7.33-7.25 (m, 2H), 3.37-3.32 (m, 2H), 2.87 (t, J=6.6Hz, 2H).

To an ice-salt bath cooled mixture of conc. HNO₃ and conc. H₂SO₄ (200mL, 1:1) was added 4-dihydro-2H-isoquinolin-1-one (15 g, 0.102 mol)dropwise over 15 min. After stirring for 2 h, the resulting mixture waspoured into ice-H₂O and stirred for 30 min. The precipitate wasfiltered, washed with H₂O, and dried in air to afford7-nitro-3,4-dihydro-2H-isoquinolin-1-one (13 g). ¹H NMR (300 MHz,DMSO-d₆) δ 8.53 (d, J=2.4 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.29 (d,J=2.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 3.44-3.39 (m, 2H), 3.04 (t, J=6.6Hz, 2H).

A suspension of 7-nitro-3,4-dihydro-2H-isoquinolin-1-one (11.6 g, 60mmol) and 10% Pd/C (1.2 g) in MeOH was stirred overnight at RT under H₂(40 psi). The mixture was filtered through Celite® and washed with MeOH.The filtrate was evaporated under vacuum to afford 8.2 g of7-amino-3,4-dihydro-2H-isoquinolin-1-one, which was used without furtherpurification.

To a suspension of 7-amino-3,4-dihydro-2H-isoquinolin-1-one (8.1 g, 50mmol) in conc. HCl (100 mL) in an ice-H₂O bath was added a solution ofNaNO₂ (3.45 g, 50 mmol) in H₂O dropwise at such a rate that the reactionmixture never rose above 5° C. A solution of SnCl₂.2H₂O(22.5 g, 0.1 mol)in conc. HCl (150 mL) was added dropwise after 30 min. The resultingmixture was stirred for another 2 h at 0° C. The precipitate wascollected by suction, washed with ether to afford7-hydrazino-3,4-dihydro-2H-isoquinolin-1-one (8.3 g), which was used forthe next reaction without further purification.

A mixture of 7-hydrazino-3,4-dihydro-2H-isoquinolin-1-one (8.0 g, 37.6mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (5.64 g, 45 mmol) in EtOH(100 mL) and conc. HCl (10 mL) was heated at reflux overnight. Afterremoval of the solvent, the residue was washed with ether to afford7-(5-amino-3-t-butyl-pyrazol-1-yl)-3,4-dihydro-2H-isoquinolin-1-onehydrochloride as a yellow solid (11.5 g, 96% yield), which was usedwithout further purification.

To a solution of7-(5-amino-3-t-butyl-pyrazol-1-yl)-3,4-dihydro-2H-isoquinolin-1-onehydrochloride (0.5 g, 1.76 mmol) in CH₂Cl₂ (25 mL) were added pyridine(0.22 mL) and trichloroethyl chloroformate (0.27 mL) at 0° C. and themixture was stirred overnight at RT. LCMS showed the reaction wasincomplete. Pyridine (0.25 mL) and TROC-Cl (0.25 mL) were added and thenthe mixture stirred at RT for 2 hours. The reaction mixture was dilutedwith CH₂Cl₂, the organic layer was washed with 3M HCl and brine, dried(Na₂SO₄) and concentrated in vacuo. The residue was dissolved in EtOAcand hexane was added. The solid was filtered to obtain2,2,2-trichloroethyl3-tert-butyl-1-(1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-ylcarbamate(0.46 g, 57% yield). MS (ESI) m/z: 458.0 (M+H⁺).

Example B30

To a solution of7-(5-amino-3-t-butyl-pyrazol-1-yl)-3,4-dihydro-2H-isoquinolin-1-onehydrochloride from Example B29 (20 g, 0.070 mol) in THF (400 mL) wasadded LAH (15 g, 0.395 mol) in portions at 0-5° C. The resulting mixturewas heated at reflux overnight, followed by the addition of 10% NaOHsolution. After stirring for 1 h at RT, Boc₂O (23 g, 0.106 mol) wasadded and the solution stirred overnight. After filtration, the filtratewas concentrated to afford the crude product, which was purified byreverse phase chromatography to give7-(5-amino-3-t-butyl-pyrazol-1-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid t-butyl ester (12 g, 75% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.32(s, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 5.32 (s, 1H),5.15 (s, 1H), 4.51 (s, 2H), 3.52 (t, J=5.6 Hz, 2H), 2.75 (t, J=5.6 Hz,2H), 1.40 (s, 9H), 1.17 (s, 9H); MS (ESI) m/z: 371 (M+H⁺).

To a stirring solution of tert-butyl7-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.50 g, 1.35 mmol) and Troc-Cl (0.19 ml, 1.38 mmol) in EtOAc (15 mL)was added satd. NaHCO₃ (2.75 ml, 2.02 mmol). The resulting biphasicmixture was stirred at RT for 5 h. The layers were separated and theorganic washed with sat'd. NaHCO₃ (1×) and brine (1×), dried (Na₂SO₄)and concentrated in vacuo to obtain tert-butyl7-(3-tert-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.69 g, 94% yield). MS (ESI) m/z: 545.0 (M+H⁺).

Example 1

A solution of Example B3 (7.0 g, 15.8 mmol), Example A2 (4.14 g, 15.8mmol) and DIEA (4.5 g, 34.9 mmol) in DMSO (70 ml) was heated in anoil-bath at 70° C. for 8 hrs. The reaction mixture was poured into water(500 ml), stirred overnight and the solids were separated by filtration.Successive crystallization of the crude product from toluene and acetoneprovided1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)ureaas a white crystalline solid (4.06 g, 46% yield). ¹H NMR (DMSO-d₆) δ8.90 (m, 2H), 8.79 (m, 1H), 8.52 (m, 2H), 8.2 (m, 3H), 7.96 (dd, J=9, 2Hz, 1H), 7.63 (dd, J=8, 4 Hz, 1H), 7.40 (br s, 1H), 7.30 (dd, J=3, 12Hz, 1H), 7.17 (m, 1H), 7.05 (d, J=9 Hz, 1H), 6.50 (s, 1H), 2.80 (d, J=5Hz), 1.32 (s, 9H); MS (ESI) m/z: 554 (M+H⁺). The free base was treatedwith 0.1 M HCl to provide1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)ureabis hydrochloride salt as a pale yellow fluffy solid (2.40 g). ¹H NMR(DMSO-d₆) δ 9.56 (s, 1H), 9.26 (m, 2H), 9.10 (d, J=8 Hz, 1H), 8.85 (m,1H), 8.55 (m, 2H), 8.46 (d, J=9 Hz, 1H), 8.33 (dd, J=9, 2 Hz, 1H), 8.11(t, J=9 Hz, 1H), 8.03 (dd, dd, J=9, 2 Hz, 1H), 7.46 (d, J=3 Hz, 1H),7.30 (dd, J=3, 12 Hz, 1H), 7.20 (dd, J=3, 6 Hz, 1H), 7.04 (brd, J=7 Hz,1H), 6.49 (s, 1H), 2.80 (d, J=4.5 Hz), 1.33 (s, 9H).

Example 2

Example B1 (142 mg, 0.33 mmol) and Et₃N (0.15 mL, 0.72 mmol) werecombined in dioxane (3 mL). DPPA (0.13 mL, 0.59 mmol) was added and thereaction mixture was stirred at RT for 90 min. Example A2 (94 mg, 0.36mmol) was added and the resultant mixture was heated to 95° C. for 4 h.The reaction mixture was concentrated in vacuo and purified by silicagel chromatography to provide benzyl6-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(95 mg, 42% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (br s, 1H), 8.84(s, 1H), 8.79 (q, J=4.8 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.20 (t, J=9.2Hz, 1H), 7.40-7.28 (m, 10H), 7.17 (dd, J=5.6, 2.8 Hz, 1H), 7.05 (m, 1H),6.40 (s, 1H), 5.14 (s, 2H), 4.66 (m, 2H), 3.68 (m, 2H), 2.91 (t, J=5.6Hz, 2H), 2.79 (d, J=4.8 Hz, 3H), 1.27 (s, 9H); MS (ESI) m/z: 692.2(M+H⁺).

A solution of benzyl6-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(93 mg, 0.13 mmol) in methanol (3 mL) was treated with 10% Pd/C (50%wet, 74 mg, 0.03 mmol) and formic acid (88%, 0.60 mL, 14 mmol). Theresultant reaction mixture was stirred for 90 min and filtered throughCelite, washing forward with methanol. The filtrate was concentrated invacuo and purified on silica gel to provide1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea(42 mg, 56% yield). The product was treated with aqueous HCl (0.1 M,0.75 mL) to provide1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)ureahydrochloride. ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (br s, 2H), 9.10 (d,J=1.8 Hz, 1H), 9.05 (s, 1H), 8.80 (m, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.15(t, J=9.1 Hz, 1H), 7.46-7.34 (m, 4H), 7.32 (dd, J=11.6, 2.8 Hz, 1H),7.18 (m, 1H), 7.05 (m, 1H), 6.39 (s, 1H), 4.33 (br s, 2H), 3.40 (2Hobscured by H₂O), 3.09 (t, J=6.0 Hz, 2H), 2.79 (d, J=5.0 Hz, 3H), 1.28(s, 9H); MS (ESI) m/z: 558.3 (M+H⁺).

Example 3

Using general method A, Example B4 (80 mg, 0.27 mmol), Example A1 (0.18g, 0.68 mmol), triethyl amine (30 mg, 0.30 mmol), and DPPA (82 mg, 0.30mmol) were combined to yield1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)ureawhich was treated with 3M HCl/EtOAc to obtain its HCl salt (125 mg, 78%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.79 (brm, 1H), 9.16 (brm, 1H),9.05 (brm, 1H), 8.93 (brm, 1H), 8.79 (brm, 1H), 8.53 (d, J=5.6 Hz, 1H),8.42 (brm, 1H), 8.33 (brm, 1H), 8.22 (brm, 1H), 7.91 (brm, 1H), 7.68(dd, J=2.4, and 14.4 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.34 (t, J=9.2 Hz,1H), 7.19 (brm, 1H), 6.49 (s, 1H), 2.79 (d, J=5.2 Hz, 3H), 1.31 (s, 9H);MS (ESI) m/z: 554.2 (M+H⁺).

Example 4

To a solution of Example B8 (0.132 g, 0.30 mmol) in THF (1.0 ml) wereadded Example A2 (0.083 g, 0.315 mmol) and 1-methylpyrrolidine (2.6 mg,0.03 mmol). The mixture was heated at 55° C. overnight. Solvent wasremoved and the residue was dissolved in MeOH (4.5 ml), to which 3MHCl/EtOAc (1.3 ml, 3.8 mmol) was added. The resulting mixture wasstirred at RT overnight, followed by heating at 55° C. for 3 h. Thereaction mixture was concentrated to dryness, diluted with sat'd. NaHCO₃(7 ml) and extracted with EtOAc (3×20 ml). The combined organic layerswas washed with sat'd. NaHCO₃ (7 ml), H₂O (7 ml) and brine (7 ml), dried(MgSO₄), concentrated in vacuo and purified by chromatography to afford1-(3-tert-butyl-1-(1H-indazol-5-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea(80 mg, 49% yield) as a white solid. This was converted to correspondingHCl salt by reacting with HCl (4.0 M in dioxane, 1.0 eq.). ¹H NMR(DMSO-d₆) δ 9.17 (s, 1H), 9.13 (s, 1H), 8.99 (m, 1H), 8.56 (d, J=5.6 Hz,1H), 8.23-8.18 (m, 2H), 7.96 (d, J=2.0 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H),7.58 (d, J=2.4 Hz, 1H), 7.49 (dd, J=8.8, 1.6 Hz, 1H), 7.32 (dd, J=11.6,2.8 Hz, 1H), 7.24 (dd, J=6.0, 3.0 Hz, 1H), 7.07 (dd, J=8.8, 1.6 Hz, 1H),6.47 (s, 1H), 2.81 (d, J=4.8 Hz, 3H), 1.30 (s, 9H); MS (ESI) m/z: 543.2(M+H⁺).

Example 5

Using general method A, Example B4 (80 mg, 0.27 mmol) and Example A6 (99mg, 0.38 mmol) were combined to provide1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea(149 mg, 99% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.97 (dd,J=4.1, 1.2 Hz, 1H), 8.77 (q, J=4.6 Hz, 1H), 8.62 (s, 1H), 8.51-8.48 (m,2H), 8.20-8.16 (m, 2H), 7.97 (d, J=8.9, 2.0 Hz, 1H), 7.63 (dd, J=8.5,4.2 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.32 (dd, J=8.7, 2.5 Hz, 1H), 7.27(d, J=2.6 Hz, 1H), 7.08 (m, 1H), 7.06 (d, J=8.7 Hz, 1H), 6.47 (s, 1H),2.78 (d, J=4.6 Hz, 3H), 2.04 (s, 3H), 1.33 (s, 9H); MS (ESI) m/z: 550.2(M+H⁺).

Example 6

Using a procedure analogous to Example 1, Example B3 (0.19 g, 0.43 mmol)and Example A7 (0.11 g, 0.43 mmol) were combined to provide1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-carbamoyl)pyridin-4-yloxy)-2-fluorophenyl)ureahydrochloride (0.160 g, 64% yield). ¹H NMR (DMSO-d₆) δ 9.55 (s, 1H),9.27-9.24 (m, 2H), 9.10 (d, J=8.8 Hz, 1H), 8.56-8.54 (m, 2H), 8.46 (d,J=9.2 Hz, 1H), 8.32 (dd, J=9.6, 2.4 Hz, 1H), 8.27 (s, 1H), 8.13 (t,J=9.2 Hz, 1H), 8.04 (dd, J=8.4, 5.2 Hz, 1H), 7.85 (s, 1H), 7.52 (d,J=2.4 Hz, 1H), 7.32 (dd, J=11.6, 2.4 Hz, 1H), 7.24 (dd, J=6.0, 2.8 Hz,1H), 7.05 (dq, J=8.8, 1.2 Hz, 1H), 6.50 (s, 1H), 1.33 (s, 9H); MS (ESI)m/z: 540.3 (M+H⁺).

Example 7

Example B3 (0.12 g, 0.27 mmol), Example A9 (63 mg, 0.27 mmol) and DIEA(77 mg, 0.60 mmol) were combined in DMSO (1 mL) and heated overnight at50-55° C. Water was added (50 mL) and the mixture was extracted withEtOAc (3×100 mL), dried (MgSO₄), concentrated in vacuo and purified bysilica gel column chromatography (EtOAc/hexane) to obtain1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylamino)pyridin-4-yloxy)phenyl)urea.The solid was treated with 0.100M HCl (2 equiv.) to obtain and1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylamino)pyridin-4-yloxy)phenyl)ureahydrochloride (52 mg, 32% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (brs,1H), 9.17 (brs, 1H), 9.06 (brm, 1H), 8.66 (brm, 1H), 8.53 (brs, 1H),8.0-8.3 (m, 4H), 7.92 (d, J=6.8 Hz, 1H), 7.74 (m, 1H), 7.35 (dd, J=2.8,and 11.6 Hz, 1H), 7.07 (m, 1H), 6.62 (d, J=6.4 Hz, 1H), 6.48 (s, 1H),6.18 (brs, 1H), 2.88 (d, J=4.8 Hz, 2H), 1.32 (s, 9H); LC-MS (EI) m/z:526.2 (M+H⁺).

Example 8

Using a procedure analogous to Example 1, Example B6 (0.178 g, 0.335mmol), Example A10 (0.0840 g, 0.352 mmol) and DIEA (0.0701 ml, 0.402mmol) were combined, purified by flash column chromatography(EtOAc/hexanes) and purified a second time by flash columnchromatography (EtOAc/CH₂Cl₂) to afford t-butyl5-(3-t-butyl-5-(3-(5-(5-chloropyridin-3-yloxy)-2-fluorophenyl)ureido)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate(0.0486 g, 23% yield) as a solid. ¹H NMR (400 MHz, acetone-d₆) δ 8.52(brd, 1H, J=2.8 Hz), 8.46 (s, 1H), 8.37 (d, 1H, J=2.0 Hz), 8.35-8.32 (m,2H), 8.24 (dt, 1H, J=0.8 and 8.8 Hz), 8.818 (dd, 1H, J=2.8 and 6.8 Hz),7.22 (dd, 1H, J=8.8 and 10.8 Hz), 6.81 (ddd, 1H, J=3.2, 4.0 and 8.8 Hz),1.73 (s, 9H), 1.34 (s, 9H); MS (ESI) m/z: 620.2 (M+H⁺).

The material from the previous step (0.0486 g, 0.078 mmol) and 4M HCl indioxane (5.0 ml) were combined at RT. A little MeOH was added to give ahomogeneous solution. The mixture was heated overnight at 40° C. Thecompleted reaction was concentrated in vacuo, dissolved in MeCN/H₂O,frozen and lyophilized to afford1-(3-t-butyl-1-(1H-indazol-5-yl)-1H-pyrazol-5-yl)-3-(5-(5-chloropyridin-3-yloxy)-2-fluorophenyl)urea(0.0475 g, 103% yield) as the bis-HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δ9.14 (s, 1H), 8.95 (s, 1H), 8.43-8.42 (m, 1H), 8.34-8.33 (m, 1H), 8.20(s, 1H), 8.00-7.97 (m, 1H), 7.88-7.87 (m, 1H), 7.70-7.67 (m, 1H),7.60-7.59 (m, 1H), 7.45-7.42 (m, 1H), 7.32-7.27 (m, 1H), 6.81-6.77 (m,1H), 6.38 (s, 1H), 1.27 (s, 9H); MS (ESI) m/z: 520.2 (M+H⁺).

Example 9

Using a procedure analogous to Example 1, Example B7 (0.300 g, 0.550mmol), Example A10 (0.138 g, 0.577 mmol) and DIEA (0.115 ml, 0.659 mmol)were combined and purified by flash column chromatography(EtOAc/hexanes) to afford tert-butyl6-(3-tert-butyl-5-(3-(5-(5-chloropyridin-3-yloxy)-2-fluorophenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.090 g, 26% yield) as a film. ¹H NMR (400 MHz, acetone-d₆) δ 8.50(brs, 1H), 8.36 (s, 1H), 8.35-8.32 (m, 2H), 8.19-8.16 (m, 1H), 7.47-7.46(m, 1H), 7.38-7.36 (m, 2H), 7.31-7.29 (m, 1H), 7.27-7.22 (m, 1H),6.83-6.79 (m, 1H), 6.46 (s, 1H), 4.63 (brs, 2H), 3.68-3.65 (m, 2H),2.89-2.86 (m, 2H), 1.50 (s, 9H), 1.32 (s, 9H); MS (ESI) m/z: 635.2(M+H⁺).

The material from the previous reaction (0.090 g, 0.14 mmol, 1.00 eq)and 4M HCl in dioxane (5.00 ml) were combined at 22° C. A little MeOHwas added to make the mixture homogeneous. After 2.5 h, the completedreaction was concentrated in vacuo, dissolved in MeCN/H₂O, frozen andlyophilized to afford1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(5-(5-chloropyridin-3-yloxy)-2-fluorophenyl)urea(76 mg, 89% yield) as the bis-HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δ 9.51(brs, 2H), 9.26 (brs, 1H), 9.22 (s, 1H), 8.42-8.41 (m, 1H), 8.33-8.32(m, 1H), 7.95-7.92 (m, 1H), 7.60-7.59 (m, 1H), 7.42-7.29 (m, 4H),6.82-6.78 (m, 1H), 6.34 (s, 1H), 4.32-4.30 (m, 2H), 3.39-3.35 (m, 2H),3.10-3.06 (m, 2H), 1.26 (s, 9H); MS (ESI) m/z: 535.2 (M+H⁺).

Example 10

Using a procedure analogous to Example 1, Example B9 (0.150 g, 0.351mmol) and Example A2 (0.101 g, 0.386 mmol) were combined to provide1-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureahydrochloride (0.126 g, 62% yield). ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H),9.18-9.15 (m, 2H), 8.92 (d, J=8.4 Hz, 1H), 8.85-8.80 (m, 1H), 8.53 (d,J=5.6 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.36 (d, J=9.2 Hz, 1H), 8.22 (dd,J=9.2, 2.4 Hz, 1H), 8.14 (t, J=9.2 Hz, 1H), 7.92 (dd, J=8.4, 4.8 Hz,1H), 7.42 (d, J=2.4 Hz, 1H), 7.31 (dd, J=11.6, 2.8 Hz, 1H), 7.19 (dd,J=5.6, 2.8 Hz, 1H), 7.04 (dd, J=8.8, 2.0 Hz, 1H), 6.45 (s, 1H), 2.96 (m,1H), 2.79 (d, J=4.8 Hz, 3H), 1.28 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 540.3(M+H⁺).

Example 11

Using a procedure analogous to Example 1, Example B10 (0.15 g, 0.363mmol) and Example A2 (0.100 g, 0.38 mmol) were combined to provide1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)ureahydrochloride (0.120 g, 58% yield). ¹H NMR (DMSO-d₆) δ 9.42 (s, 1H),9.21-9.18 (m, 2H), 8.96 (d, J=8.4 Hz, 1H), 8.87-8.82 (m, 1H), 8.53 (d,J=5.6 Hz, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.38 (d, J=9.2 Hz, 1H), 8.25 (dd,J=9.2, 1.6 Hz, 1H), 8.14 (t, J=8.8 Hz, 1H), 7.95 (dd, J=8.0, 4.8 Hz,1H), 7.43 (d, J=2.0 Hz, 1H), 7.31 (dd, J=12.0, 2.4 Hz, 1H), 7.19 (dd,J=5.2, 2.0 Hz, 1H), 7.05 (dt, J=8.8, 1.6 Hz, 1H), 6.44 (s, 1H), 2.79 (d,J=4.8 Hz, 3H), 2.64 (q, J=7.6 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H); MS (ESI)m/z: 526.2 (M+H⁺).

Example 12

Using a procedure analogous to Example 1, Example B3 (0.195 g, 0.441mmol), Example A10 (0.111 g, 0.464 mmol) and DIEA (0.0923 ml, 0.530mmol) were combined and purified first by flash column chromatography(EtOAc/hexanes) and then by reverse phase chromatography (MeCN (w/0.1%TFA)/H₂O (w/0.1% TFA)) to provide an aqueous solution of the TFA salt ofthe desired product. The aqueous residue was treated with satd. NaHCO₃(pH 8) and extracted with EtOAc (3×). The combined organics were washedwith brine (1×), dried (MgSO₄), and evaporated to afford product (0.0258g, 11% yield) as the free base. The free base was treated with certified0.1N HCl (0.97 ml, 2.0 eq) to afford1-(3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(5-(5-chloropyridin-3-yloxy)-2-fluorophenyl)urea(0.0262 g, 10% yield) as the bis-HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δ9.33 (s, 1H), 9.22-9.21 (m, 1H), 9.14-9.13 (m, 1H), 8.83-8.81 (m, 1H),8.42-8.41 (m, 1H), 8.36 (brs, 1H), 8.33-8.29 (m, 2H), 8.15-8.12 (m, 1H),7.94-7.91 (m, 1H), 7.88-7.84 (m, 1H), 7.59-7.57 (m, 1H), 7.34-7.28 (m,1H), 6.82-6.78 (m, 1H), 6.46 (s, 1H), 1.30 (s, 9H); MS (ESI) m/z: 531.0(M+H⁺).

Example 13

Using a procedure analogous to Example 1, Example B3 (100 mg, 0.226mmol), DIEA (73 mg, 0.566 mmol) and Example A18 (63 mg, 0.25 mmol) werecombined to yield1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(2-(methylthio)pyrimidin-4-yloxy)phenyl)ureahydrochloride (61 mg, 50% yield). ¹H-NMR (DMSO-d₆) δ 1.30 (s, 9H), 2.50(s, 3H), 6.47 (s, 1H), 6.76 (d, 1H), 6.86-6.90 (m, 1H), 7.29-7.34 (m,1H), 7.92-7.98 (m, 2H), 8.20-8.23 (m, 1H), 8.37 (d, 1H), 8.44 (s, 1H),8.50 (d, 1H), 8.95 (d, 1H), 9.19-9.20 (m, 1H), 9.28 (s, 1H), 9.46 (s,1H); MS (ESI) m/z: 544.2 (M+H⁺).

Example 14

Using a procedure analogous to Example 1, Example B3 (0.10 g, 0.23mmol), Example A12 (53 mg, 0.23 mmol) and DIEA (64 mg, 0.50 mmol) werecombined and purified by reverse phase column chromatography to obtain1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-(hydroxymethyl)pyridin-3-yloxy)phenyl)ureaTFA salt. The residue was dissolved in 3M HCl and co-evaporated withisopropyl alcohol (3×). EtOAc was added to the residue and the solid wasfiltered, washed with EtOAc, and dried under vacuum to obtain1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-(hydroxymethyl)pyridin-3-yloxy)phenyl)ureaHCl salt (40 mg, 34% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (brm, 1H),9.05 (brm, 1H), 8.63 (brm, 1H), 8.32 (brm, 1H), 8.23 (brm, 2H), 8.03 (m,1H), 7.90 (m, 1H), 7.73 (brm, 1H), 7.56 (m, 2H), 7.28 (dd, J=9.2, 12.4Hz, 1H), 6.74 (m, 1H), 6.44 (s, 1H), 4.60 (m, 2H), 1.30 (s, 9H); MS(ESI) m/z: 527.2 (M+H⁺).

Example 15

Using a procedure analogous to Example 1, Example B9 (0.120 g, 0.281mmol) and Example A7 (0.0763 g, 0.309 mmol) were combined to provide1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureahydrochloride (0.101 g, 65% yield). ¹H NMR (DMSO-d₆) δ 9.23 (s, 1H),9.11-9.08 (m, 2H), 8.77 (d, J=4.8 Hz, 1H), 8.53 (d, J=6.0 Hz, 1H), 8.35(d, J=2.0 Hz, 1H), 8.29 (d, J=8.8 Hz, 1H), 8.18-8.11 (m, 3H), 7.84-7.80(m, 1H), 7.75 (s, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.31 (dd, J=11.6, 2.4 Hz,1H), 7.20 (dd, J=6.0, 2.4 Hz, 1H), 7.05 (dd, J=9.6, 2.8 Hz, 1H), 6.45(s, 1H); MS (ESI) m/z: 526.2 (M+H⁺).

Example 16

Using a procedure analogous to Example 1, Example B3 (85 mg, 0.19 mmol),Example A13 (42 mg, 0.19 mmol) and DIEA (55 mg, 0.42 mmol) were combinedin DMSO (1 mL) and heated overnight at 50-55° C. Water was added (50 mL)and the mixture was extracted with EtOAc (3×100 mL), dried (MgSO₄),concentrated in vacuo and purified by silica gel column chromatographyto obtain1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-methylpyridin-3-yloxy)phenyl)urea.The product treated with 0.10M aq HCl solution to obtain1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-methylpyridin-3-yloxy)phenyl)ureasalt HCl salt (56 mg, 52% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (brs,1H), 9.27 (d, J=2.4 Hz, 1H), 9.11 (dd, J=1.6, and 4.8 Hz, 1H), 8.77 (d,J=8.0 Hz, 1H), 8.50 (d, J=3.2 Hz, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.29 (d,J=9.2 Hz, 1H), 8.11 (dd, J=2.4, and 9.2 Hz, 1H), 7.94 (dd, J=3.2, and6.8 Hz, 1H), 7.83 (m, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.32 (dd, J=9.2, 10.8Hz, 1H), 6.79 (m, 1H), 6.44 (s, 1H), 2.61 (s, 3H), 1.30 (s, 9H); MS(ESI) m/z: 511.2 (M+H⁺).

Example 17

Using a procedure analogous to Example 1, Example B9 (213 mg, 0.50mmol), Example A6 (145 mg, 0.56 mmol) and DIEA (0.09 mL, 0.517 mmol)were combined in DMF (2 mL) to provide1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea(194 mg, 73% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.07 (s, 1H), 8.97(dd, J=4.2, 1.8 Hz, 1H), 8.76 (q, J=4.9 Hz, 1H), 8.64 (s, 1H), 8.51-8.48(m, 2H), 8.19-8.16 (m, 2H), 7.97 (dd, J=9.0, 2.4 Hz, 1H), 7.63 (dd,J=8.3, 4.2 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.33 (dd, J=8.9, 2.6 Hz,1H), 7.28 (d, J=2.6 Hz, 1H), 7.10-7.04 (m, 2H), 6.43 (s, 1H), 2.95 (m,1H), 2.78 (d, J=4.9 Hz, 3H), 2.04 (s, 3H), 1.28 (d, J=6.7 Hz, 6H); MS(ESI) m/z: 536.2 (M+H⁺).

Example 18

mCPBA (1.07 g of ˜70%, 4.34 mmol) was added to a solution of Example A18(545 mg, 2.17 mmol) in CH₂Cl₂ (15 mL) and the solution was stirred atRT. The mixture was washed with saturated sodium bicarbonate (3×20 mL)and brine (30 mL), dried (Na₂SO₄) and concentrated in vacuo to yield0.65 g of a tan foam, which proved to be a mixture of the sulfoxide andsulfone, and which was used as is. In 2.0N methylamine/THF (22 mL) wasplaced the crude sulfoxide/sulfone mixture (0.61 g, 2.2 mmol) withstirring overnight at 40° C. The mixture was cooled to RT, diluted withethyl acetate (25 mL), washed with 5% citric acid (25 mL), saturatedsodium bicarbonate (25 mL) and brine (25 mL), dried (Na₂SO₄),concentrated in vacuo and purified by reverse phase chromatography toyield 4-(3-amino-4-fluorophenoxy)-N-methylpyrimidin-2-aminetrifluoroacetic acid salt (301 mg, 60% yield). MS (ESI) m/z: 235.0(M+H⁺).

In DMSO (2 mL) was placed Example B3 (159 mg, 0.359 mmol), DIEA (139 mg,1.08 mmol) and 4-(3-amino-4-fluorophenoxy)-N-methylpyrimidin-2-aminetrifluoroacetic acid salt (150 mg, 0.431 mmol). The mixture was warmedto 50° C. overnight, then diluted with ethyl acetate (25 mL), washedwith 5% citric acid (50 mL), saturated sodium bicarbonate (50 mL) andbrine (50 mL), dried (Na₂SO₄), concentrated in vacuo and purified bycolumn chromatography to yield1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(2-(methylamino)pyrimidin-4-yloxy)phenyl)urea(93 mg, 49% yield). ¹H-NMR (DMSO-d₆) 1.31 (s, 9H), 2.54-2.86 (br d, 3H),6.46 (s, 1H), 6.57-6.61 (br m, 1H), 6.91-6.93 (br m, 1H), 7.32-7.37 (m,1H), 7.94-8.05 (m, 2H), 8.23-8.33 (m, 2H), 8.40 (d, 1H), 8.48 (s, 1H),8.98 (d, 1H), 9.19-9.21 (m, 1H), 9.43-9.47 (br m, 1H), 9.68-9.73 (br m,1H); MS (ESI) m/z: 527.2 (M+H⁺).

Example 19

Using a procedure analogous to Example 1, Example B9 (85 mg, 0.20 mmol),Example A9 (46 mg, 0.20 mmol) and DIEA (57 mg, 0.44 mmol) were combinedin DMSO (1 mL) to obtain1-(2-fluoro-4-(2-(methylamino)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea.The product was treated with 0.100M aq HCl solution to obtain1-(2-fluoro-4-(2-(methylamino)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureaHCl salt (52 mg, 48% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.17 (s, 1H),9.14 (brs, 1H), 8.98 (dd, J=1.2, and 4.0 Hz, 1H), 8.50 (d, J=8.4 Hz,1H), 8.42 (brs, 1H), 8.20 (d, J=2.8 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H),7.97 (dd, J=2.4, and 9.2 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.64 (dd,J=4.0, and 8.4 Hz, 1H), 7.34 (dd, J=2.4, and 11.6 Hz, 1H), 7.07 (dd,J=1.2, and 8.8 Hz, 1H), 6.60 (d, J=6.4 Hz, 1H), 6.43 (s, 1H), 6.17 (brs,1H), 2.95 (m, 1H), 2.87 (d, J=4.4 Hz, 3H), 1.27 (d, J=6.8 Hz, 6H); MS(ESI) m/z: 512.3 (M+H⁺).

Example 20

Using a procedure analogous to Example 1, Example B10 (0.13 g, 0.314mmol), Example A7 (0.086 g, 0.346 mmol) and DIEA (0.12 mL, 0.69 mmol)were dissolved in DMSO (1.5 mL) and the mixture was heated at 55° C.overnight to afford1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.088 g, 55% yield). This was converted to corresponding HCl salt byreacting with HCl (4.0 M HCl/dioxane, 1.0 eq.). ¹H NMR (DMSO-d₆) δ 9.37(s, 1H), 9.18-9.15 (m, 2H), 8.90 (d, J=8.0 Hz, 1H), 8.54 (d, J=5.6 Hz,1H), 8.43 (s, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.22-8.12 (m, 3H), 7.91 (m,1H), 7.78 (s, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.31 (dd, J=12, 2.0 Hz, 1H),7.21 (dd, J=5.2, 1.4 Hz, 1H), 7.05 (d, J=9.2 Hz, 1H), 6.44 (s, 1H), 2.64(q, J=7.6 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 512.3 (M+H⁺).

Example 21

Using a procedure analogous to Example 1, Example B3 (198 mg, 373 mmol),DIEA (121 mg, 0.933 mmol) and Example A21 (117 mg, 0.448 mmol) werecombined to yield1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-(methylcarbamoyl)pyridin-3-yloxy)phenyl)urea(140 mg, 67% yield) as the hydrochloride salt. ¹H-NMR (DMSO-d₆) δ 1.30(s, 9H), 2.81 (d, 3H), 6.45 (s, 1H), 6.81-6.83 (m, 1H), 7.30-7.35 (m,1H), 7.43-7.46 (m, 1H), 7.91-8.02 (m, 3H), 8.19-8.21 (m, 1H), 8.34-8.43(m, 3H), 8.65-8.66 (m, 1H), 8.91 (d, 1H), 9.17-9.19 (m, 1H), 9.28 (br s,1H), 9.44 (s, 1H); MS (ESI) m/z: 554.2 (M+H⁺).

Example 22

Using a procedure analogous to Example 1, Example B14 (0.125 g, 0.291mmol) and Example A7 (0.079 g, 0.320 mmol) were combined to provide1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(5-chloro-2-(quinolin-6-yl)phenyl)ureahydrochloride (0.070 g, 43% yield). ¹H NMR (DMSO-d₆) δ 9.20 (d, J=3.6Hz, 1H), 9.04 (d, J=1.6 Hz, 1H), 8.92 (d, J=8.0 Hz, 1H), 8.54-8.52 (m,2H), 8.36 (d, J=9.2 Hz, 1H), 8.32 (d, J=1.6 Hz, 1H), 8.23 (t, J=8.8 Hz,1H), 8.18-8.17 (m, 2H), 8.02 (dd, J=8.4, 1.6 Hz, 1H), 7.93-7.90 (m, 1H),7.76 (s, 1H), 7.43-7.39 (m, 2H), 7.31-7.26 (m, 2H), 7.20 (dd, J=5.6, 2.4Hz, 1H), 7.06 (dd, J=8.8, 1.2 Hz, 1H); MS (ESI) m/z: 528.0 (M+H⁺).

Example 23

Using a procedure analogous to Example 1, Example B9 (35 mg, 0.02 mmol),Example A14 (47 mg, 0.20 mmol) and DIEA were combined in DMSO and heatedovernight at 60° C. to obtain1-(2-fluoro-4-(2-methoxypyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureaHCl salt (54 mg, 49% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (brs, 1H),9.13 (brs, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.74 (s, 1H), 8.35 (dd, J=1.6,and 8.4 Hz, 1H), 8.25 (m, 1H), 7.90 (s, 1H), 7.74 (d, J=8.4 Hz, 1H),7.71 (brs, 1H), 7.29 (m, 2H), 6.46 (s, 1H), 4.31 (q, J=7.2 Hz, 2H), 2.66(s, 3H), 1.29 (s, 9H), 1.22 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 556.3(M+H⁺).

Example 24

Using a procedure analogous to Example 1, Example B19 (150 mg, 0.329mmol) and Example A2 (94 mg, 0.362 mmol) were combined to provide1-(3-tert-butyl-1-(2-methylquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)ureahydrochloride (113 mg, 60% yield). ¹H-NMR (DMSO-d₆) δ 1.33 (s, 9H), 2.79(d, 3H), 3.00 (s, 3H), 6.49 (s, 1H), 7.02-7.04 (m, 1H), 7.19-7.20 (m,1H), 7.30 (d, 1H), 7.45 (s, 1H), 8.01 (d, 1H), 8.07-8.09 (m, 1H),8.34-8.37 (m, 1H), 8.50-8.57 (m, 3H), 8.85-8.87 (m, 1H), 9.10 (d, 1H),9.29 (s, 1H), 9.61 (s, 1H); MS (ESI) m/z: 568.2 (M+H⁺).

Example 25

Using a procedure analogous to Example 1, Example B9 (120 mg, 0.28mmol), Example A20 (80 mg, 0.29 mmol), and DIEA (110 mg, 0.84 mmol) werecombined to yield1-(2-fluoro-5-(6-(trifluoromethyl)pyridin-3-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureahydrochloride (62 mg, 40% yield). ¹H-NMR (DMSO-d₆) δ 1.25 (d, 6H), 2.93(pen, 1H), 6.41 (s, 1H), 6.85-6.88 (m, 1H), 7.32-7.37 (m, 1H), 7.51-7.54(m, 1H), 7.87-7.90 (m, 2H), 7.96-7.98 (m, 1H), 8.16-8.18 (m, 1H), 8.33(d, 1H), 8.40 (s, 1H), 8.52 (s, 1H), 8.87 (d, 1H), 9.15-9.16 (m, 1H),9.28 (s, 1H), 9.42 (s, 1H); MS (ESI) m/z: 551.2 (M+H⁺).

Example 26

Using a procedure analogous to Example 1, Example B9 (0.200 g, 0.468mmol) and Example A15 (0.113 g, 0.491 mmol) were combined to provide1-(4-(2-cyanopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.238 g, 100%). MS (ESI) m/z: 508.3 (M+H⁺)

1-(4-(2-Cyanopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.108 g, 0.221 mmol) and N-acetylcysteine (0.072 g, 0.441 mmol) weredissolved in MeOH (0.3 mL). Ammonium acetate (0.041 g, 0.0.529 mmol) wasadded and the reaction mixture was heated at 60° C. under N₂ overnight.The completed reaction was diluted with H₂O (10 ml), basified by K₂CO₃,extracted with EtOAc (2×30 mL) and THF (20 mL). The combined organiclayers were washed with brine (20 mL), dried (MgSO₄), concentrated invacuo and purified by chromatography to afford1-(4-(2-carbamimidoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.019 g, 17% yield) as a white solid. This was converted tocorresponding HCl salt by reacting with HCl (4.0 M HCl/dioxane, 1.0eq.). ¹H NMR (DMSO-d₆) δ 9.57 (s, 2H), 9.36-9.34 (m, 2H), 9.20 (d, J=1.2Hz, 1H), 9.09 (dd, J=4.4, 1.2 Hz, 1H), 8.74 (d, J=8.0 Hz, 1H), 8.68 (d,J=5.2 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.28 (d, J=9.2 Hz, 1H), 8.18-8.10(m, 2H), 7.92 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.4, 4.8 Hz, 1H), 7.32-7.26(m, 2H), 7.05 (dd, J=8.8, 1.2 Hz, 1H), 6.44 (s, 1H), 2.97-2.93 (m, 1H),1.28 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 525.3 (M+H⁺).

Example 27

Using a procedure analogous to Example 1, Example B7 (159 mg, 0.291mmol), DIEA (45 mg, 0.35 mmol) and Example A34 (74 mg, 0.35 mmol) werecombined to give tert-butyl6-(3-tert-butyl-5-(3-(3-cyano-5-(pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(83 mg, 47% yield). MS (ESI) m/z: 608.3 (M+H⁺).

In CH₂Cl₂ (8 mL) was placed tert-butyl6-(3-tert-butyl-5-(3-(3-cyano-5-(pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(83 mg, 0.14 mmol). HCl (g) was bubbled into reaction mixture until thesolution was saturated and the solution was then stirred at RT for 4hrs. Concentration in vacuo gave a solid which was triturated with ether(10 mL). The solid was collected by filtration, washed with ether (2 mL)and dried to afford1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-cyano-5-(pyridin-3-yloxy)phenyl)ureahydrochloric acid salt (69 mg, 93% yield). ¹H NMR (300 MHz, DMSO-d₆) δ1.26 (s, 9H), 3.06-3.09 (m, 2H), 3.35-3.40 (m, 2H), 4.28-4.30 (m, 2H),6.33 (s, 1H), 7.23-7.24 (m, 1H), 7.31-7.34 (m, 1H), 7.39-7.47 (m, 4H),7.63-7.67 (m, 2H), 7.77-7.78 (m, 1H), 8.52-8.54 (m, 1H), 8.59 (m, 1H),8.93 (s, 1H), 9.42-9.43 (m, 2H), 10.16 (s, 1H); MS (ESI) m/z: 527.2(M+H⁺).

Example 28

Using a procedure analogous to Example 1, Example A35 (95 mg, 0.428mmol), DIEA (158 mg, 1.22 mmol) and Example B3 (180 mg, 0.407 mmol) werecombined to give1-(5-(2-aminopyrimidin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureahydrochloride salt (102 mg, 48% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 1.31(s, 9H), 6.46 (s, 1H), 6.65 (d, J=6.8 Hz, 1H), 6.91-6.94 (m, 1H),7.32-7.37 (m, 1H), 7.91-7.94 (m, 1H), 7.97-8.00 (m, 1H), 8.20-8.23 (m,1H), 8.31-8.33 (m, 1H), 8.36-8.39 (m, 1H), 8.45-8.46 (m, 1H), 8.92-8.94(m, 1H), 9.18 (m, 1H), 9.45 (m, 1H), 9.66 (s, 1H), NH2 missing; MS (ESI)m/z: 513.3 (M+H⁺).

Example 29

Using a procedure analogous to Example 1, Example B9 (0.200 g, 0.468mmol) and Example A15 (0.113 g, 0.491 mmol) in presence of DIEA (0.179mL, 0.1.03 mmol) were combined to afford1-(4-(2-cyanopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.238 g, 100%) as a colorless oil. It was converted to correspondingHCl salt by reacting with HCl (4.0 M in dioxane, 1.0 eq.). ¹H NMR (400MHz, DMSO-d₆) δ 9.19 (s, 1H), 9.09-9.08 (m, 2H), 8.73 (d, J=8.0 Hz, 1H),8.60 (d, J=6.0 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H),8.16 (t, J=9.2 Hz, 1H), 8.10 (dd, J=9.2, 2.4 Hz, 1H), 7.80 (dd, J=8.0,4.4 Hz, 1H), 7.72 (d, J=2.8 Hz, 1H), 7.31 (dd, J=11.6, 2.8 Hz, 1H), 7.23(dd, J=5.6, 2.8 Hz, 1H), 7.05 (dd, J=9.2, 2.8 Hz, 1H), 6.45 (s, 1H),2.95 (m, 1H), 1.27 (d, J=7.2 Hz, 6H); MS (ESI) m/z: 508.3 (M+H⁺).

Example 30

Using a procedure analogous to Example 1, Example B3 (0.2 g, 0.453 mmol)and Example A29 (0.158 g, 0.453 mmol) were combined in DMSO (4 mL) at70° C. in presence of DIEA (0.176 g, 1.36 mmol) to provide1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-((tert-butyldimethylsilyloxy)methyl)pyridin-4-yloxy)-2-fluorophenyl)urea(0.12 g, 43% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.02 (brs, 1H), 8.86 (d,J=8.5 Hz, 1H), 7.65 (m, 3H), 7.27 (dd, J=8, 4.4 Hz, 1H), 6.99 (s, 1H),6.89 (brd, J=9.0 Hz, 1H), 6.73 (dd, J=12, 2.5 Hz, 1H), 6.65 (s, 1H),6.60 (m, 1H), 4.71 (s, 2H), 1.36 (s, 9H), 0.85 (s, 9H), 0.05 (s, 6H); MS(ESI) m/z: 641.3 (M+H⁺).

A solution of1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-((tert-butyldimethylsilyloxy)methyl)pyridin-4-yloxy)-2-fluorophenyl)urea(0.12 g, 0.19 mmol) in THF (2 ml) was treated with TBAF (1.0 ml, 1.0 Msolution in THF) at RT for 1 hour. Water (10 ml) was added and theseparated solid was filtered, washed with water and dried to givedesilylated product1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(hydroxymethyl)pyridin-4-yloxy)phenyl)ureaas a white solid (0.090 g, 91% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.01(brs, 1H), 8.97 (dd, J=4.2, 1.6 Hz, 2H), 8.50 (brd, J=8.3 Hz, 1H), 8.36(d, J=5.5 Hz, 2H), 8.18 (m, 2H), 7.97 (dd, J=9, 2 Hz, 1H), 7.63 (dd,J=9, 4.4 Hz, 1H), 7.22 (dd, J=12, 2.5 Hz, 1H), 6.99 (m, 1H), 6.93 (d,J=2.5 Hz, 1H), 6.82 (dd, J=5.7, 2.5 Hz, 1H), 6.48 (s, 1H), 5.40 (t, J=6Hz, 1H), 4.50 (d, J=8 Hz, 2H), 1.32 (s, 9H); MS (ESI) m/z: 527.2 (M+H⁺).The free base was converted to hydrochloride salt. ¹H NMR (400 MHz,DMSO-d₆) δ 9.31 (brs, 1H), 9.23 (m, 1H), 9.07 (dd, J=4.2, 1.6 Hz, 1H),8.70 (brd, J=8.3 Hz, 1H), 8.65 (d, J=6.8 Hz, 2H), 8.32 (d, J=2 Hz, 1H),8.27 (d, J=9 Hz, 1H), 8.22 (d, J=9 Hz, 1H), 8.09 (dd, J=9, 2.3 Hz, 1H),7.75 (dd, J=8, 4.5 Hz, 1H), 7.43-7.37 (m, 2H), 7.34 (d, 2.8 Hz, 1H),7.12 (m, 1H), 6.48 (s, 1H), 4.77 (s, 2H), 1.32 (s, 9H); MS (ESI) m/z:527.2 (M+H⁺).

Example 31

Using a procedure analogous to Example 4, Example B25 (0.30 g, 0.89mmol) and Example A31 (0.26 g, 0.98 mmol) in presence ofN-methylpyrrolidine (catalytic amount) were combined to afford1-(2-fluoro-4-(2-(isopropylamino)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.26 g, 54% yield). The product was treated with methanesulfonic acidto afford1-(2-fluoro-4-(2-(isopropylamino)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureamesylate salt (260 mg, 88% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (m,1H), 9.01 (s, 1H), 8.96 (dd, J=1.6, and 4.0 Hz, 1H), 8.49 (brd, J=8.4Hz, 1H), 8.33 (brm, 1H), 8.17 (m, 2H), 7.95 (dd, J=2.8, and 9.2 Hz, 1H),7.87 (d, J=7.6 Hz, 1H), 7.63 (d, J=4.4, and 8.4 Hz, 1H), 7.33 (dd,J=2.8, and 11.6 Hz, 1H), 7.06 (m, 1H), 6.61 (dd, J=2.4, and 7.2 Hz, 1H),6.41 (s, 1H), 6.09 (brs, 1H), 3.81 (m, 1H), 2.91 (m, 1H), 2.30 (s, 3H),1.25 (d, J=6.8 Hz, 6H), 1.13 (d, J=6.0 Hz, 6H); MS (ESI) m/z: 540.3(M+H⁺).

Example 32

Using general method A, Example B20 (0.0643 g, 0.226 mmol) and ExampleA7 (0.168 g, 0.678 mmol) were combined to afford1-(3-tert-butyl-1-(H-imidazo[1,2-a]pyridin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)urea(0.071 g, 59%) as a white solid. It was converted to corresponding HClsalt by reacting with HCl (4.0 M in dioxane, 1.0 eq.). ¹H NMR (400 MHz,DMSO-d₆) δ 9.48 (s, 1H), 9.33 (d, J=0.8 Hz, 1H), 9.13 (d, J=1.6 Hz, 1H),8.53 (d, J=5.2 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H),8.17-8.09 (m, 4H), 7.72 (s, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.32 (dd,J=12.0, 2.8 Hz, 1H), 7.20 (dd, J=5.6, 2.8 Hz, 1H), 7.05 (dd, J=9.2, 1.6Hz, 1H), 6.49 (s, 1H), 1.32 (s, 9H); MS (ESI) m/z: 529.3 (M+H⁺).

Example 33

Using a procedure analogous to Example 1, Example B9 (100 mg, 0.23 mmol)and Example A12 (55 mg, 0.23 mmol) in presence of DIEA (90 μL, 0.51mmol) were combined to afford1-(2-fluoro-5-(6-(hydroxymethyl)pyridin-3-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(30 mg, 25% yield). The product was treated with methanesulfonic acid toafford1-(2-fluoro-5-(6-(hydroxymethyl)pyridin-3-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureamesylate salt (23 mg, 65% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (brs,1H), 9.10 (m, 1H), 9.06 (m, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.34 (s, 1H),8.25 (d, J=1.6 Hz, 1H), 8.21 (d, J=9.2 Hz, 1H), 8.03 (dd, J=2.4, and 9.2Hz, 1H), 7.91 (dd, J=2.8, and 6.4 Hz, 1H), 7.75 (dd, J=4.8, and 8.4 Hz,1H), 7.58 (s, 1H), 7.30 (m, 1H), 6.75 (m, 1H), 6.40 (s, 1H), 4.61 (s,2H), 2.92 (m, 1H), 2.32 (s, 3H), 1.25 (d, J=6.8 Hz, 6H); MS (ESI) m/z:513.3 (M+H⁺).

Example 34

Using a procedure analogous to Example B19 step 2, Example A2 (1.00 g,3.83 mmol) and 2,2,2-trichloroethyl carbonochloridate (1.30 g, 6.12mmol) were combined to give 2,2,2-trichloroethyl2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylcarbamate. MS (ESI)m/z: 436.0, 438.0 (M+H).

A solution of Example B28 (57 mg, 0.213 mmol), 2,2,2-trichloroethyl2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylcarbamate (102 mg,0.235 mmol) and DIEA (110 mg, 0.853 mmol) in DMSO (1.5 mL) was placedwas warmed to 60° C. overnight. It was then treated with additional2,2,2-trichloroethyl2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylcarbamate (˜200mg), warmed to 60° C. overnight. The reaction was diluted with ethylacetate (25 mL) and 5% citric acid (20 mL). The organic phase wasseparated, washed with saturated sodium bicarbonate (20 mL) and brine(20 mL), dried (Na₂SO₄), concentrated in vacuo and purified bychromatography (Si-25 column, MeOH/EtOAc) to afford impure product.Repurification via reverse phase chromatography (C18-25 column,CH₃CN/H₂O) gave a residue which was treated with 1N sodium hydroxide (3mL) and extracted with ethyl acetate (2×20 mL). The combined organicphases were dried (Na₂SO₄), concentrated in vacuo and treated with 4NHCl/dioxane (0.1 mL) to afford1-(3-tert-butyl-1-(quinoxalin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)ureahydrochloric acid salt (14 mg, 12% yield). ¹H NMR (300 MHz, DMSO-d₆) δ1.31 (s, 9H), 2.77 (d, 3H), 6.47 (s, 1H), 7.00-7.05 (m, 1H), 7.15-7.18(m, 1H), 7.26-7.28 (m, 1H), 7.39 (m, 1H), 7.65 (m, 1H), 8.08-8.13 (m,2H), 8.21-8.25 (m, 2H), 8.50 (m, 1H), 8.78 (m, 1H), 8.97-9.03 (m, 3H),9.13 (s, 1H); MS (ESI) m/z: 555.2 (M+H⁺).

Example 35

Using a procedure analogous to Example 1, Example B9 (0.145 g, 0.339mmol) and Example A27 (0.087 g, 0.323 mmol) in presence of DIEA (0.124mL, 0.710 mmol) were combined to afford1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.112 g, 63%) as a white foam. It was converted to correspondingmesylate salt by reacting with MsOH (1.0 eq.). ¹H NMR (400 MHz, DMSO-d₆)δ 9.10-9.03 (m, 3H), 8.63-8.52 (m, 4H), 8.26-8.20 (m, 2H), 8.03 (d,J=3.6 Hz, 1H), 7.78-7.70 (m, 2H), 7.40 (d, J=10.8 Hz, 1H), 7.14-7.09 (m,2H), 6.44 (s, 1H), 2.95 (m, 1H), 2.33 (s, 3H), 1.27 (d, J=7.2 Hz, 6H);MS (ESI) m/z: 549.3 (M+H⁺).

Example 36

Example B22 (0.310 g, 0.715 mmol), Example A2 (0.187 g, 0.715 mmol) andDIEA (0.274 ml, 1.57 mmol) were combined in DMSO (3 ml) and stirred at70° C. After 18 h, the completed reaction was cooled to RT, diluted withbrine and extracted with EtOAc (3×). The combined organics were washedwith brine (2×), dried (MgSO₄), evaporated and purified by flash columnchromatography (EtOAc/hexanes) to afford the free base (84.1 mg, 22%yield). The free base thus obtained was treated with certified 0.1N HCl(3.1 ml, 2.0 eq) to afford1-(1-(benzo[d]thiazol-6-yl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea(45 mg) as the bis-HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H),9.00 (s, 2H), 8.81 (q, J=4.8 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.39 (d,J=1.6 Hz, 1H), 8.24 (d, J=8.80 Hz, 1H), 8.19 (t, J=9.2 Hz, 1H), 7.70(dd, J=2.4 and 8.8 Hz, 1H), 7.42 (d, J=2.4 Hz), 7.31 (dd, J=3.2 and 12.0Hz, 1H), 7.18 (dd, J=2.8 and 6.0 Hz, 1H), 7.06 (ddd, J=1.2, 2.8 and 8.8Hz, 1H), 6.42 (s, 1H), 2.92 (septet, J=7.2 Hz, 1H), 2.79 (d, J=4.8 Hz,3H), 1.26 (d, J=7.2 Hz, 6H); MS (ESI) m/z: 546.3 (M+H⁺).

Example 37

Example B23 (0.200 g, 0.464 mmol), Example A2 (0.121 g, 0.464 mmol) andi-Pr₂NEt (0.178 ml, 1.02 mmol) were combined in DMSO (2 ml) and stirredwith heating at 70° C. After 18 h, the completed reaction was cooled toRT, diluted with brine and extracted with EtOAc (3×). The combinedorganics were washed with brine (2×), dried (MgSO₄), concentrated invacuo and purified by flash column chromatography (EtOAc/hexanes toEtOAc to THF) to afford impure product. This was purified a second timeby reverse phase chromatography (MeCN (w/0.1% TFA)/H₂O (w/0.1% TFA)) toafford desired product (110 mg, 36% yield) as the TFA salt followinglyophilization. The TFA salt thus obtained was dissolved in THF andshaken orbitally with MP-carbonate resin (110 mg) for 2 h. Thesupernatant was decanted away and the beads washed with THF (2×). Thecombined decants were concentrated, diluted with MeCN/H₂O and thentreated with certified 0.1N HCl (3.3 ml, 2.0 eq) to afford1-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(1-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-5-yl)urea(31 mg) as the bis-HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (brs, 1H),9.11 (s, 1H), 9.07 (s, 1H), 8.76 (brq, J=4.8 Hz, 1H), 8.50 (d, J=5.6 Hz,1H), 8.11 (t, J=9.2 Hz, 1H), 8.06 (d, J=8.8 Hz), 7.98 (d, J=2.0 Hz, 1H),7.78 (m, 1H), 7.37 (d, J=2.8 Hz, 1H), 7.28 (dd, J=2.4 and 11.2 Hz, 1H),7.16 (dd, J=2.4 and 5.6 Hz, 1H), 7.02 (ddd, J=1.2, 2.8 and 8.8 Hz, 1H),6.38 (s, 1H), 4.08 (s, 3H), 2.92 (septet, J=6.8 Hz, 1H), 2.76 (d, J=4.8Hz, 3H), 1.24 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 543.2 (M+H⁺).

Example 38

Using general method A, Example B21 (0.0.054 g, 0.20 mmol) and ExampleA2 (0.16 g, 0.60 mmol) were combined to afford1-(1-(H-imidazo[1,2-a]pyridin-6-yl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea(0.045 g, 43% yield) as a white solid. It was converted to correspondingmesylate salt by reacting with MsOH (1.0 eq.). ¹H NMR (400 MHz, DMSO-d₆)δ 9.19 (m, 1H), 8.49 (d, J=6.0 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.24(dd, J=9.6, 3.0 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 8.08 (d, J=10.0 Hz,1H), 8.01 (t, J=8.8 Hz, 1H), 7.53 (d, J=3.5 Hz, 1H), 7.12 (dd, J=6.0,3.0 Hz, 1H), 7.06 (dd, J=11.6, 2.8 Hz, 1H), 6.96 (m, 1H), 6.45 (s, 1H),3.01 (m, 1H), 2.94 (s, 3H), 2.70 (s, 3H), 1.33 (d, J=6.4 Hz, 6H); MS(ESI) m/z: 529.3 (M+H⁺).

Example 39

Using general method A, Example B21 (0.030 g, 0.11 mmol) and Example A7(0.082 g, 0.33 mmol) were combined to afford1-(1-(H-imidazo[1,2-a]pyridin-6-yl)-3-isopropyl-1H-pyrazol-5-yl)-3-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)urea(0.0245 g, 43% yield) as a white solid. It was converted tocorresponding HCl salt by reacting with HCl (4.0 M in dioxane, 1.0 eq.).¹H NMR (400 MHz, DMSO-d₆) δ 9.26 (d, J=0.8 Hz, 1H), 8.69 (d, J=6.4 Hz,1H), 8.38 (d, J=1.6 Hz, 1H), 8.26 (dd, J=9.6, 1.2 Hz, 1H), 8.20-8.11 (m,3H), 7.96 (s, 1H), 7.48 (d, J=5.6 Hz, 1H), 7.23 (dd, J=11.6, 2.8 Hz,1H), 7.10 (d, J=9.2 Hz, 1H), 6.51 (s, 1H), 3.03 (m, 1H), 1.37 (d, J=6.8Hz, 6H); MS (ESI) m/z: 515.2 (M+H⁺).

Example 40

Using a procedure analogous to Example 1, Example A39 (63 mg, 0.29 mmol)and Example B9 (122 mg, 0.29 mmol) were combined to provide1-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureacontaminated with 2,2,2-trichloroethanol (56 mg, 28% yield). ¹H NMR (400MHz, DMSO-d₆) δ 8.99-8.96 (m, 2H), 8.93 (d, J=1.5 Hz, 1H), 8.49 (m, 1H),8.19-8.16 (m, 2H), 8.10 (t, J=9.2 Hz, 1H), 7.95 (dd, J=9.1, 2.3 Hz, 1H),7.80 (d, J=5.8 Hz, 1H), 7.63 (dd, J=8.3, 4.0 Hz, 1H), 7.15 (dd, J=11.8,2.8 Hz, 1H), 6.95 (m, 1H), 6.44 (s, 1H), 6.13 (dd, J=5.9, 2.2 Hz, 1H),5.94 (s, 2H), 5.82 (d, J=2.0 Hz, 1H), 2.94 (m, 1H), 1.27 (d, J=6.8 Hz,6H); MS (ESI) m/z: 498.2 (M+H⁺).

A solution of the above1-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(44 mg, 0.061 mmol theory) and pyridine (0.30 mL, 3.7 mmol) in CH₂Cl₂ (1mL) was treated with acetic anhydride (0.040 mL, 0.39 mmol). Thereaction was stirred for 60 h and then partitioned between EtOAc and 2 Maq Na₂CO₃. The organic layer was washed with water and brine. Theaqueous phases were back extracted with EtOAc. The combined organicphases were dried (Na₂SO₄), concentrated in vacuo and purified byreverse-phase chromatography to provide1-(4-(2-acetamidopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(25 mg, 76% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (s, 1H), 9.01 (s,1H), 8.96-8.94 (m, 2H), 8.49 (m, 1H), 8.18-8.11 (m, 4H), 7.95 (dd,J=8.8, 2.4 Hz, 1H), 7.64-7.59 (m, 2H), 7.21 (dd, J=11.8, 2.7 Hz, 1H),6.98 (m, 1H), 6.65 (dd, J=5.8, 2.4 Hz, 1H), 6.43 (s, 1H), 2.93 (m, 1H),2.03 (s, 3H), 1.26 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 540.3 (M+H⁺).

Example 41

Using as procedure analogous to Example 4, Example B25 (100 mg, 0.30mmol) and Example A30 (74 mg, 0.30 mmol) in presence ofN-methylpyrrolidine (catalytic amount) were combined to afford1-(4-(2-(ethylamino)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(70 mg, 45% yield). The product was treated with methanesulfonic acid toafford1-(4-(2-(ethylamino)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureamesylate salt (71 mg, 87% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (m,1H), 9.01 (s, 1H), 8.97 (dd, J=1.6, and 4.0 Hz, 1H), 8.49 (brd, J=8.4Hz, 1H), 8.37 (brs, 1H), 8.17 (m, 2H), 7.95 (dd, J=2.4, and 8.8 Hz, 1H),7.88 (d, J=7.2 Hz, 1H), 7.63 (d, J=4.4, and 8.4 Hz, 1H), 7.33 (dd,J=2.8, and 11.6 Hz, 1H), 7.06 (m, 1H), 6.61 (dd, J=2.0, and 7.2 Hz, 1H),6.41 (s, 1H), 6.13 (brs, 1H), 3.23 (m, 2H), 2.92 (m, 1H), 2.28 (s, 3H),1.25 (d, J=6.8 Hz, 6H), 1.13 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 526.2(M+H⁺).

Example 42

Using a procedure analogous to Example 1, Example B9 (295 mg, 0.69 mmol)and Example A40 (214 mg, 0.763 mmol) were combined in DMF (3 mL) toprovide1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea(278 mg, 72% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.94 (dd,J=4.2, 1.6 Hz, 1H), 8.59 (s, 1H), 8.45 (dd, J=8.6, 1.0 Hz, 1H), 8.29 (d,J=6.0 Hz, 1H), 8.20 (s, 1H), 8.15-8.13 (m, 2H), 7.94 (dd, J=9.1, 2.4 Hz,1H), 7.91 (s, 1H), 7.60 (dd, J=8.5, 4.1 Hz, 1H), 7.40 (d, J=2.3 Hz, 1H),7.27 (dd, J=8.6, 2.4 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 6.99 (d, J=8.8 Hz,1H), 6.45 (dd, J=5.7, 2.4 Hz, 1H), 6.39 (s, 1H), 3.83 (s, 3H), 2.92 (m,1H), 2.05 (s, 3H), 1.25 (d, J=6.9 Hz, 6H); MS (ESI) m/z: 559.2 (M+H⁺).

Example 43

Using a procedure analogous to Example 1, Example B3 (0.711 g, 1.66mmol) and Example A28 (0.450 g, 1.58 mmol) in presence of DIEA (0.61 mL,3.48 mmol) were combined to afford1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.431 g, 48% yield) as a white solid. It was converted to correspondingmesylate salt by reacting with MsOH (1.0 eq.). ¹H NMR (400 MHz, DMSO-d₆)δ 9.08-9.04 (m, 3H), 8.66 (d, J=8.8 Hz, 1H), 8.57-8.54 (m, 2H),8.26-8.16 (m, 4H), 8.05 (dd, J=9.2, 2.4 Hz, 1H), 7.75 (q, J=4.4 Hz, 1H),7.64 (s, 1H), 7.37 (dd, J=11.6, 2.0 Hz, 1H), 7.12-7.08 (m, 2H), 6.41 (s,1H), 3.90 (s, 3H), 2.92 (m, 1H), 2.33 (s, 3H), 1.24 (d, J=7.2 Hz, 6H);MS (ESI) m/z: 563.3 (M+H⁺).

Example 44

Using a procedure analogous to Example 4, Example B26 (100 mg, 0.29mmol) and Example A31 (75 mg, 0.29 mmol) in presence ofN-methylpyrrolidine (catalytic amount) were combined to afford1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isopropylamino)pyridin-4-yloxy)phenyl)urea(59 mg, 32% yield). The product was treated with methanesulfonic acid toafford1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isopropylamino)pyridin-4-yloxy)phenyl)ureamesylate salt (63 mg, 93% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (m,1H), 9.00 (s, 1H), 8.98 (m, 1H), 8.54 (brd, J=8.4 Hz, 1H), 8.35 (brm,1H), 8.17 (m, 2H), 7.97 (dd, J=2.4, and 9.2 Hz, 1H), 7.86 (d, J=7.2 Hz,1H), 7.66 (d, J=4.4, and 8.4 Hz, 1H), 7.33 (dd, J=2.8, and 11.6 Hz, 1H),7.05 (m, 1H), 6.61 (dd, J=2.4, and 6.8 Hz, 1H), 6.45 (s, 1H), 6.08 (brs,1H), 3.81 (m, 1H), 2.29 (s, 3H), 1.29 (s, 9H), 1.13 (d, J=6.0 Hz, 6H);MS (ESI) m/z: 554.2 (M+H⁺).

Example 45

Using a procedure analogous to Example 1, Example B10 (0.060 g, 0.15mmol) and Example A28 (0.041 g, 0.15 mmol) in presence of DIEA (0.056mL, 0.32 mmol) were combined to afford1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea(47.6 mg, 60% yield) as a white foam. It was converted to correspondingmesylate salt by reacting with MsOH (1.0 eq.). ¹H NMR (400 MHz, DMSO-d₆)δ 9.03-8.95 (m, 3H), 8.55-8.48 (m, 3H), 8.19-8.13 (m, 3H), 7.95 (dd,J=9.2, 2.4 Hz, 1H), 7.64 (dd, J=8.4, 4.4 Hz, 1H), 7.55 (s, 1H), 7.32(dd, J=12.0, 2.8 Hz, 1H), 7.07-7.01 (m, 2H), 6.36 (s, 1H), 3.86 (s, 3H),2.56 (q, J=7.2 Hz, 2H), 2.25 (s, 3H), 1.18 (t, J=7.6 Hz, 3H); MS (ESI)m/z: 549.3 (M+H⁺).

Example 46

Using general method A, Example B27 (77 mg, 0.28 mmol) and Example A2(150 mg, 0.57 mmol) in presence of DPPA (67 μL, 0.31 mmol) and Et₃N (44μL, 0.31 mmol) were combined to afford1-(1-(benzo[d]oxazol-5-yl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea(105 mg, 70% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.96 (d, J=2.0 Hz, 1H),8.88 (s, 1H), 8.86 (s, 1H), 8.77 (q, J=4.8 Hz, 1H), 8.49 (d, J=6.0 Hz,1H), 8.16 (t, J=9.2 Hz, 1H), 7.94 (dd, J=3.2 and 5.2 Hz, 1H), 7.57 (dd,J=2, and 8.8 Hz, 1H), 7.38 (d, J=2.8 Hz, 1H), 7.28 (dd, J=2.4 and 11.6Hz, 1H), 7.14 (dd, J=2.8 and 5.6 Hz, 1H), 7.03 (m, 1H), 6.37 (s, 1H),2.76 (d, J=4.8 Hz, 3H), 1.23 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 530.2(M+H⁺).

Example 47

To a suspension of 5-amino-2-fluorobenzonitrile (1.00 g, 7.38 mmol) inconc HCl (15 mL) at 0° C. was added a solution of NaNO₂ (0.64 g, 9.28mmol) in water (15 mL) slowly over 15 min. The resultant mixture wasstirred for 90 min at 0° C. A solution comprised of SnCl₂.2H₂O (3.37 g,14.9 mmol), conc HCl (5 mL) and water (5 mL) was added drop wise over 20min. The mixture was stirred for 2 h at 0° C., and was extracted withEtOAc (4×25 mL). The aqueous portion was cooled with an ice bath andcautiously treated with 70 mL of 3 M NaOH (70 mL) to a final pH of 5.The aqueous was extracted with EtOAc (2×50 mL). All organics werecombined and concentrated in vacuo to afford a brown oil (2.58 g), whichwas combined with pivaloylacetonitrile (1.00 g, 8.0 mmol) in isopropanol(15 mL). The resultant solution was heated to reflux for 28 h. Thereaction mixture was concentrated in vacuo, diluted with EtOAc (30 mL)and washed with water (20 mL), satd aq NaHCO₃ (20 mL), water (20 mL) andbrine (20 mL). The aqueous was further extracted with EtOAc (2×20 mL).The combined organics were dried (MgSO₄), concentrated in vacuo andpurified by chromatography on silica gel to provide5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-2-fluorobenzonitrile (1.24 g,65% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (m, 1H), 7.97 (m, 1H), 7.61(t, J=9.0 Hz, 1H), 5.43 (s, 1H), 5.42 (s, 2H); MS (ESI) m/z: 259.3(M+H⁺).

A solution 5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-2-fluorobenzonitrile(86 mg, 0.33 mmol) and acetone oxime (37 mg, 0.50 mmol) in DMAc (1 mL)was treated with potassium tert-butoxide (56 mg, 0.50 mmol). Thereaction mixture was stirred 45 min at RT. The mixture was diluted withEtOAc (30 mL), washed with water (10 mL) and brine (2×10 mL), dried(Na₂SO₄), concentrated in vacuo and purified via silica gelchromatography to provide propan-2-oneO-2-cyano-4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl oxime (47 mg,45% yield). ¹H NMR (400 MHz, Acetone-d₆) δ 7.93-7.89 (m, 2H), 7.63 (dd,J=8.8, 0.8 Hz, 1H), 5.52 (s, 1H), 4.87 (s, 2H), 2.17 (s, 3H), 2.08)s,3H), 1.26 (s, 9H); MS (ESI) m/z: 312.3 (M+H⁺).

A solution of propan-2-oneO-2-cyano-4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl oxime (47 mg,0.15 mmol) in ethyl acetate (5 mL) was treated with 2 M aq Na₂CO₃ (0.67mL) and isopropenyl chloroformate (0.050 mL, 0.46 mmol). The reactionwas stirred at RT. After 2 h, additional isopropenyl chloroformate (0.1mL, 0.92 mmol) was added. Afterl h, additional isopropenyl chloroformate(0.1 mL, 0.92 mmol) and 2 M aq Na₂CO₃ (0.5 mL, 1 mmol) were added. Afteranother hour, the reaction was diluted with EtOAc (10 mL), washed withwater (10 mL) and brine (10 mL), dried (MgSO₄) and concentrated in vacuoto provide the isopropenyl carbamate of propan-2-oneO-2-cyano-4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl oxime (62 mg,58% yield) that was used without further purification. MS (ESI) m/z:396.2 (M+H⁺).

The isopropenyl carbamate from the previous step (60 mg, 0.15 mmol),Example A2 (40 mg, 0.15 mmol) and N-methylpyrrolidine (1 mg, 0.015 mmol)were combined in THF (1 mL) and heated to 55° C. overnight. The reactionwas concentrated and chromatographed to provide the corresponding urea(97 mg, >100% yield) as a dark foam. MS (ESI) m/z: 599.2 (M+H⁺).

The above urea was dissolved in ethanol and treated with 3 M aq HCl (0.5mL). After 24 h, another 0.5 mL of 3 M aq HCL was added and the stirringwas continued for 3 days. The reaction mixture was partitioned aqueous 2M Na₂CO₃ and EtOAc. The organic layer was washed with sat aq NaHCO3,water, and brine, dried (Na₂SO₄), concentrated in vacuo and purified bysilica gel chromatography and recrystallization from acetone to provide1-(1-(3-aminobenzo[d]isoxazol-5-yl)-3-tert-butyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea(33 mg, 39% yield over 2 steps). ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (d,J=2.2 Hz, 1H), 8.86 (s, 1H), 7.77 (q, J=4.8 Hz, 1H), 8.50 (d, J=5.4 Hz,1H), 8.20 (t, J=9.3 Hz, 1H), 7.99 (d, J=1.2 Hz, 1H), 7.64-7.59 (m, 2H),7.37 (d, J=2.4 Hz, 1H), 7.29 (dd, J=11.9, 2.6 Hz, 1H), 7.15 (dd, J=5.6,2.6 Hz, 1H), 7.03 (m, 1H), 6.55 (s, 2H), 6.41 (s, 1H), 2.77 (d, J=4.7Hz, 3H), 1.27 (s, 9H); MS (ESI) m/z: 559.2 (M+H⁺).

Example 48

Using a procedure analogous to Example 1, Example B9 (0.175 g, 0.41mmol) and Example A42 (0.097 g, 0.389 mmol) were combined to afford1-(2-fluoro-5-(6-nitropyridin-3-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.129 g, 63% yield) as a light yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ8.94 (dd, J=4.4, 2.0 Hz, 1H), 8.48 (d, J=8.4 Hz, 1H), 8.31 (d, J=8.8 Hz,1H), 8.26 (d, J=2.8 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.11 (d, J=2.4 Hz,1H), 8.00 (m, 1H), 7.91 (dd, J=9.2, 2.4 Hz, 1H), 7.63 (m, 1H), 7.58 (dd,J=8.8, 2.8 Hz, 1H), 7.22 (m, 1H), 6.84 (m, 1H), 6.46 (s, 1H), 2.98 (m,1H), 1.30 (d, J=7.2 Hz, 6H); MS (ESI) m/z: 528.3 (M+H⁺).

1-(2-fluoro-5-(6-nitropyridin-3-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.129 g, 0.245 mmol) was dissolved in MeOH (2.0 mL), to which NH₄Cl(0.131 g, 2.45 mmol) and zinc power (0.160 g, 2.45 mmol) were added andthe reaction mixture was stirred at RT for 4 h. The reaction mixture wasfiltered through Celite and washed with methanol (30 mL) and EtOAc (50mL). The filtrate was concentrated in vacuum, partitioned between EtOAc(30 mL) and water (20 mL). The separated organic phase was washed withbrine (10 mL), dried (MgSO₄) and concentrated to afford1-(5-(6-aminopyridin-3-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.0495 g, 41% yield) as a white foam. MS (ESI) m/z: 498.2 (M+H⁺).

1-(5-(6-aminopyridin-3-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.0495 g, 0.099 mmol) was dissolved in DCM (1.0 mL), to which pyridine(0.49 mL, 6.0 mmol) and acetic anhydride (0.066 mL, 0.65 mmol) wereadded. The reaction mixture was stirred at RT for 12 h. The completedreaction was quenched with 2M NaHCO₃ (12 mL) and extracted with EtOAc(25 mL). The organic layer was washed with H₂O (15 mL) and brine (10mL), dried (MgSO₄), concentrated in vacuo and purified by chromatographyto afford1-(5-(6-acetamidopyridin-3-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(0.0234 g, 44% yield) as a yellow foam. It was converted tocorresponding mesylate salt by reacting with MsOH (1.0 eq.). ¹H NMR (400MHz, DMSO-d₆) δ 10.54 (s, 1H), 9.09 (s, 1H), 9.07-9.04 (m, 2H), 8.65 (d,J=8.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.11-8.07(m, 2H), 8.02 (dd, J=8.8, 2.4 Hz, 1H), 7.85 (m, 1H), 7.75 (m, 1H), 4.48(dd, J=8.8, 3.2 Hz, 1H), 7.24 (m, 1H), 6.67 (m, 1H), 6.40 (s, 1H), 2.92(m, 1H), 2.31 (s, 3H), 2.08 (s, 3H), 1.24 (d, J=7.2 Hz, 6H); MS (ESI)m/z: 540.0 (M+H⁺).

Example 49

Using a procedure analogous to Example 1, Example B24 (150 mg, 0.26mmol) and Example A28 (74 mg, 0.26 mmol) in presence of DIEA (90 μL,0.52 mmol) were combined to afford benzyl6-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(100 mg, 56% yield).

To a solution of benzyl6-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(100 mg, 0.14 mmol) in methanol/EtOAc (1:1, 10 mL) was added 10% Pd/C.The solution was stirred overnight under H₂ (1 atm) at RT. The solutionwas filtered and concentrated in vacuo to obtain1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea(73 mg, 90% yield) ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (brs, 1H), 8.02 (m,1H), 8.35 (d, J=5.6 Hz, 1H), 8.25 (s, 1H), 8.15 (dt, J=2.4, and 8.8,1H), 7.95 (s, 1H), 7.1-7.3 (m, 3H), 7.99 (m, 1H), 6.65 (m, 1H), 6.36 (d,J=2.8 Hz, 1H), 3.95 (m, 1H), 3.84 (s, 3H), 3.53 (m, 1H), 3.01 (m, 1H),2.88 (m, 1H), 2.79 (m, 1H), 2.60 (m, 1H), 1.25 (s, 9H); MS (ESI) m/z:581.3 (M+H⁺).

Example 50

Using a procedure analogous to Example 1, Example B29 (0.20 g, 0.43mmol) and Example A27 (118 mg, 0.43 mmol) were combined to afford1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)urea(123 mg, 47% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (brs, 1H), 8.83(s, 1H), 8.33 (d, J=5.6 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 8.07 (m, 2H),7.85 (d, J=2.0 Hz, 1H), 7.57 (dd, J=2.4, and 8.0 Hz, 1H), 7.42 (d, J=8.0Hz, 1H), 7.31 (brs, 1H), 7.18 (dd, J=2.4, and 12.0 Hz, 1H), 6.95 (m,1H), 6.65 (m, 1H), 6.33 (s, 1H), 3.35 (m, 2H), 2.91 (m, 2H), 1.22 (s,9H); MS (ESI) m/z: 581.3 (M+H⁺).

Example 51

Using a procedure analogous to Example 1, Example B30 (0.20 g, 0.37mmol) and Example A27 (100 mg, 0.37 mmol) were combined to affordtert-butyl7-(5-(3-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)ureido)-3-tert-butyl-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(130 mg, 53% yield) which was treated with 4.0 M HCl/dioxane (2 mL) andit was stirred at RT for 4 hours. The solid was filtered, washed withethyl acetate, and dried under vacuum to obtain1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)ureaHCl salt (120 mg, 96% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.51 (brs,2H), 9.27 (brs, 1H), 9.21 (brs, 1H), 8.69 (brs, 2H), 8.54 (d, J=7.2 Hz,1H), 8.22 (t, J=9.2 Hz, 1H), 7.84 (m, 1H), 7.3-7.5 (m, 4H), 7.13 (m 1H),7.10 (dd, J=2.4, and 6.4 Hz, 1H), 6.37 (s, 1H), 4.38 (m, 2H), 3.38 (m,2H), 3.05 (m, 2H), 1.28 (s, 9H); MS (ESI) m/z: 567.3 (M+H).

Example 52

Using a procedure analogous to Example 1, Example A36 (110 mg, 0.363mmol) and Example B10 (150 mg, 0.363 mmol) were combined and purified bychromatography (Si-25 column, methanol/ethyl acetate) to give1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureaas a white foam (66 mg, 32% yield). ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 1.27 (t, 3H), 2.65 (q, 2H), 3.89 (s, 3H), 6.46(s, 1H), 6.74-6.76 (m, 1H), 7.22 (t, 1H), 7.29 (s, 1H), 7.65-7.68 (s,1H), 7.97-8.02 (m, 3H), 8.20-8.22 (m, 2H), 8.31 (s, 1H), 8.40-8.42 (m,1H), 8.50-8.53 (m, 1H), 9.00-9.01 (m, 1H), 9.11 (s, 1H), 9.19 (s, 1H);MS (ESI) m/z: 567.0 (M+H⁺).

Example 53

Using a procedure analogous to Example 1, Example A38 (108 mg, 0.363mmol) and Example B10 (150 mg, 0.363 mmol) were combined and purified bychromatography (Si-25 column, methanol/ethyl acetate) to give1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureaas a white foam (78 mg, 38% yield). ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 1.29 (t, 3H), 2.09 (s, 3H), 2.67 (q, 2H), 3.91(s, 3H), 6.47 (s, 1H), 6.59-6.61 (m, 1H), 7.00-7.02 (m, 1H), 7.22 (s,1H), 7.67-7.70 (m, 1H), 7.99-8.10 (m, 3H), 8.22-8.24 (m, 2H), 8.30 (s,1H), 8.39 (d, 1H), 8.53-8.55 (m, 1H), 9.00-9.03 (m, 2H), 9.10 (s, 1H);MS (ESI) m/z: 563.3 (M+H⁺).

Example 54

Using a procedure analogous to Example 1, Example B3 (0.10 g, 0.23 mmol)and Example A32 (56 mg, 0.23 mmol) in the presence of DIEA (68 μL) werecombined to afford1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(5-chloropyridin-3-yloxy)-5-cyanophenyl)urea(39 mg, 32% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.98 (dd,J=2.0 and 4.4 Hz, 1H), 8.82 (s, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.49 (m,1H), 8.45 (d, J=2.4 Hz, 1H), 8.17 (m, 2H), 7.97 (dd, J=2.8 and 9.2 Hz,1H), 7.84 (t, J=2.0 Hz, 1H), 7.70 (t, J=1.6 Hz, 1H), 7.65 (dd, J=4.0 and8.0 Hz, 1H), 7.45 (t, J=2.0 Hz, 1H), 7.31 (m, 1H), 6.48 (s, 1H), 2.50(s, 3H), 1.34 (s, 9H); MS (ESI) m/z: 538.0 (M+H⁺).

Example 55

Using a procedure analogous to Example 1, Example B3 (0.10 g, 0.23 mmol)and Example A33 (51 mg, 0.23 mmol) in presence of DIEA (68 μL) werecombined to afford1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-cyano-5-(6-methylpyridin-3-yloxy)phenyl)urea(31 mg, 27% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.43 (s, 1H), 8.98 (dd,J=2.0 and 4.4 Hz, 1H), 8.74 (s, 1H), 8.48 (m, 1H), 8.33 (d, J=2.8 Hz,1H), 8.16 (m, 2H), 7.96 (dd, J=2.8 and 9.2 Hz, 1H), 7.63 (m, 2H), 7.50(dd, J=2.8 and 8.0 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.29 (t, J=2.0 Hz,1H), 7.17 (m, 1H), 6.46 (s, 1H), 2.50 (s, 3H), 1.33 (s, 9H); MS (ESI)m/z: 518.0 (M+H⁺).

Example 56

Using a procedure analogous to Example 1, Example A41 (15 mg, 0.055mmol) and Example B9 (24 mg, 0.056 mmol) were combined to provide1-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(9 mg, 29% yield) ¹H NMR (400 MHz, DMSO-d₆) δ 13.36 (s, 1H), 9.09 (s,1H), 9.07 (s, 1H), 8.95 (m, 1H), 8.50-8.45 (m, 2H), 8.17-8.12 (m, 2H),8.01 (dd, J=6.8, 2.9 Hz, 1H), 7.92 (dd, J=9.0, 2.1 Hz, 1H), 7.61 (dd,J=8.2, 4.1 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 7.27 (dd, J=11.0, 8.9 Hz,1H), 6.85 (m, 1H), 6.40 (s, 1H), 2.89 (m, 1H), 1.22 (d, J=6.8 Hz, 6H);MS (ESI) m/z: 550.2 (M+H⁺).

The following examples were prepared by the methods described in Schemes1-17, General Method A, the above Examples and the methods described inWO 2006/071940, filed Dec. 23, 2005, incorporated by reference:1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,1-(3-tert-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-tert-butyl-1H-pyrazol-5-yl)-3-(2-chloro-5-(5-fluoropyridin-3-yloxy)phenyl)urea,1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(pyridin-3-yloxy)phenyl)urea,1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,4-difluoro-5-(pyridin-3-yloxy)phenyl)urea,1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,4-difluoro-5-(pyridin-3-yloxy)phenyl)urea,1-(3-tert-butyl-1-(1H-indazol-5-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(pyridin-3-yloxy)phenyl)urea,1-(5-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-3-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(2-hydroxyethylamino)pyridin-4-yloxy)phenyl)urea,1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-chloro-5-(6-cyanopyridin-3-yloxy)-2-fluorophenyl)urea,1-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-3-(1-(quinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-cyclopentyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,1-(3-cyclobutyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(5-(6-cyanopyridin-3-yloxy)-2-fluorophenyl)urea,1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(methylamino)pyridin-4-yloxy)phenyl)urea,1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(pyridin-3-yloxy)phenyl)urea,1-(2-fluoro-5-(6-methylpyridin-3-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylamino)pyridin-4-yloxy)phenyl)urea,1-(3-tert-butyl-1-(1H-indazol-5-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(2-(methylamino)pyrimidin-4-yloxy)phenyl)urea,1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(4-chloro-2-(quinolin-6-yl)phenyl)urea,1-(1-(1H-indazol-5-yl)-3-isopropyl-1H-pyrazol-5-yl)-3-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)urea,1-(3-tert-butyl-1-(2-methylquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)urea,1-(4-(2-carbamoylpyridin-4-yloxy)-3-methylphenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(2-methylquinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(2-methylquinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(4-(2-(dimethylamino)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylamino)pyridin-4-yloxy)phenyl)urea,1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-carbamoylpyridin-4-yloxy)-3-methylphenyl)urea,1-(5-(2-aminopyrimidin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(2-methylquinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(2-fluoro-4-(2-(methylamino)pyrimidin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(2-fluoro-5-(6-(methylcarbamoyl)pyridin-3-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,1-(3-tert-butyl-1-(2-methylquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylamino)pyridin-4-yloxy)phenyl)urea,1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-methyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinoxalin-6-yl)-1H-pyrazol-5-yl)urea,1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinoxalin-6-yl)-1H-pyrazol-5-yl)urea,1-(1-(benzo[d]oxazol-5-yl)-3-tert-butyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-methylphenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(3-fluoro-4-(2-(isopropylamino)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(isopropylamino)pyridin-4-yloxy)-3-methylphenyl)urea,1-(4-(2-(cyclopentylamino)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureaand1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-methyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea.

The following examples are prepared by the methods described in Schemes1-17, General Method A, the above Examples and the methods described inWO 2006/071940, filed Dec. 23, 2005, incorporated by reference:1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-yloxy)phenyl)urea,1-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-isopropyl-3-(quinolin-6-yl)-1H-pyrazol-4-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-isopropyl-4-(quinolin-6-yl)-1H-pyrrol-3-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-isopropyl-5-methyl-3-(quinolin-6-yl)-1H-pyrazol-4-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-isopropyl-5-(quinolin-6-yl)oxazol-4-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-isopropyl-5-(quinolin-6-yl)thiazol-4-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-isopropyl-2-(quinolin-6-yl)furan-3-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-isopropyl-2-(quinolin-6-yl)thiophen-3-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(4-isopropyl-1-(quinolin-6-yl)-1H-imidazol-2-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-isopropyl-2-(quinolin-6-yl)-1H-pyrrol-3-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(4-isopropyl-1-(quinolin-6-yl)-1H-pyrrol-2-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-methyl-2-(quinolin-6-yl)pyridin-3-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-isopropyl-3-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-4-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-isopropyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrol-3-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-isopropyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)oxazol-4-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-isopropyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)thiazol-4-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-isopropyl-2-(1,2,3,4-tetrahydroisoquinolin-6-yl)furan-3-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-isopropyl-2-(1,2,3,4-tetrahydroisoquinolin-6-yl)thiophen-3-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(4-isopropyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-imidazol-2-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-isopropyl-2-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrol-3-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(4-isopropyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrol-2-yl)urea,1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-methyl-2-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)urea,4-(3-fluoro-4-(3-(1-isopropyl-3-(quinolin-6-yl)-1H-pyrazol-4-yl)ureido)phenoxy)-N-methylpicolinamide,4-(3-fluoro-4-(3-(1-isopropyl-4-(quinolin-6-yl)-1H-pyrrol-3-yl)ureido)phenoxy)-N-methylpicolinamide,4-(3-fluoro-4-(3-(2-isopropyl-5-(quinolin-6-yl)oxazol-4-yl)ureido)phenoxy)-N-methylpicolinamide,4-(3-fluoro-4-(3-(2-isopropyl-5-(quinolin-6-yl)thiazol-4-yl)ureido)phenoxy)-N-methylpicolinamide,4-(3-fluoro-4-(3-(5-isopropyl-2-(quinolin-6-yl)thiophen-3-yl)ureido)phenoxy)-N-methylpicolinamide,4-(3-fluoro-4-(3-(4-isopropyl-1-(quinolin-6-yl)-1H-imidazol-2-yl)ureido)phenoxy)-N-methylpicolinamide,4-(3-fluoro-4-(3-(5-isopropyl-2-(quinolin-6-yl)-1H-pyrrol-3-yl)ureido)phenoxy)-N-methylpicolinamide,4-(3-fluoro-4-(3-(4-isopropyl-1-(quinolin-6-yl)-1H-pyrrol-2-yl)ureido)phenoxy)-N-methylpicolinamide,4-(3-fluoro-4-(3-(5-methyl-2-(quinolin-6-yl)pyridin-3-yl)ureido)phenoxy)-N-methylpicolinamide,4-(3-fluoro-4-(3-(5-isopropyl-2-(quinolin-6-yl)furan-3-yl)ureido)phenoxy)-N-methylpicolinamide,1-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylphenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,145-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylphenyl)-3-(1-(benzo[d]oxazol-5-yl)-3-isopropyl-1H-pyrazol-5-yl)urea,1-(2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(1-(benzo[d]oxazol-5-yl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea,1-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylphenyl)-3-(1-(imidazo[1,2-a]pyridin-6-yl)-3-isopropyl-1H-pyrazol-5-yl)urea,1-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-3-(1-(imidazo[1,2-a]pyridin-6-yl)-3-isopropyl-1H-pyrazol-5-yl)urea.

Section 3

Abl kinase (Seq. ID No. 1) Assay

Activity of Abl kinase (Seq. ID no. 1) was determined by following theproduction of ADP from the kinase reaction through coupling with thepyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al.Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH(thus the decrease at A_(340nm)) was continuously monitoredspectrophometrically. The reaction mixture (100 μl) contained Abl kinase(1 nM. Abl from deCode Genetics), peptide substrate (EAIYAAPFAKKK, 0.2mM), MgCl₂ (10 mM), pyruvate kinase (4 units), lactate dehydrogenase(0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 90 mMTris buffer containing 0.2% octyl-glucoside and 3.5% DMSO, pH 7.5. Testcompounds were incubated with Abl (Seq. ID no. 1) and other reactionreagents at 30 C for 2 h before ATP (500 μM) was added to start thereaction. The absorption at 340 nm was monitored continuously for 2hours at 30° C. on Polarstar Optima plate reader (BMG). The reactionrate was calculated using the 1.0 to 2.0 h time frame. Percentinhibition was obtained by comparison of reaction rate with that of acontrol (i.e. with no test compound). IC₅₀ values were calculated from aseries of percent inhibition values determined at a range of inhibitorconcentrations using software routines as implemented in the GraphPadPrism software package.

pAbl Kinase Assay

Activity of pAbl kinase (Seq. ID no. 1) was determined by following theproduction of ADP from the kinase reaction through coupling with thepyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al.Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH(thus the decrease at A_(340nm)) was continuously monitoredspectrophometrically. The reaction mixture (100 μl) contained pAblkinase (2 nM. pAbl from deCode Genetics), peptide substrate(EAIYAAPFAKKK (SEQ ID No: 3), 0.2 mM), MgCl₂ (10 mM), pyruvate kinase (4units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM),and NADH (0.28 mM) in 90 mM Tris buffer containing 0.2% octyl-glucosideand 3.5% DMSO, pH 7.5. Test compounds were incubated with pAbl (SEQ. IDNO: 1) and other reaction reagents at 30 C for 2 h before ATP (500 μM)was added to start the reaction. The absorption at 340 nm was monitoredcontinuously for 2 hours at 30° C. on Polarstar Optima plate reader(BMG). The reaction rate was calculated using the 1.0 to 2.0 h timeframe. Percent inhibition was obtained by comparison of reaction ratewith that of a control (i.e. with no test compound). IC₅₀ values werecalculated from a series of percent inhibition values determined at arange of inhibitor concentrations using software routines as implementedin the GraphPad Prism software package. pAbl was obtained as aphosphorylated form of the enzyme used in the Abl assay (see above).

Abl(T315I) (Seq. ID no. 2) Kinase Assay

Activity of Abl(T315I) (SEQ. ID NO: 2) kinase was determined byfollowing the production of ADP from the kinase reaction throughcoupling with the pyruvate kinase/lactate dehydrogenase system (e.g.,Schindler, et al. Science (2000) 289, 1938-1942). In this assay, theoxidation of NADH (thus the decrease at A_(340nm)) was continuouslymonitored spectrophometrically. The reaction mixture (100 μl) containedAbl(T315I) kinase (Seq. ID no. 2) (6 nM. Abl(T315I) from decodeGenetics), peptide substrate (EAIYAAPFAKKK (SEQ. ID NO: 3), 0.2 mM),MgCl₂ (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 90 mM Trisbuffer containing 0.2% octyl-glucoside and 3.5% DMSO, pH 7.5. Testcompounds were incubated with Abl(T315I) and other reaction reagents at30 C for 2 h before ATP (500 μM) was added to start the reaction. Theabsorption at 340 nm was monitored continuously for 2 hours at 30° C. onPolarstar Optima plate reader (BMG). The reaction rate was calculatedusing the 1.0 to 2.0 h time frame. Percent inhibition was obtained bycomparison of reaction rate with that of a control (i.e. with no testcompound). IC₅₀ values were calculated from a series of percentinhibition values determined at a range of inhibitor concentrationsusing software routines as implemented in the GraphPad Prism softwarepackage.

Abl kinase (SEQ. ID NO: 1)MSYYHHHHHHDYDIPTTENLYFQGAMDPSSPNYDKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVYELMRACWQWNPSDRPSFAEIHQAF ETMFQESSISDEVEKELGKRGTAbl(T315I) kinase (SEQ. ID NO: 2)MSYYHHHHHHDYDIPTTENLYFQGAMDPSSPNYDKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQLLGVCTREPPFYIIIEFMTYGNLLDYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVYELMRACWQWNPSDRPSFAEIHQAF ETMRGT

Cell Culture

BaF3 cells (parental or transfected with the following: wild typebcr-Abl or bcr-Abl point mutants T315I, E255K, Y253F, M351T) wereobtained from Professor Richard Van Etten (New England Medical Center,Boston, Mass.). Briefly, cells were grown in RPMI 1640 supplemented with10% characterized fetal bovine serum (HyClone, Logan, Utah) at 37degrees Celsius, 5% CO₂, 95% humidity. Cells were allowed to expanduntil reaching 80% saturation at which point they were subcultured orharvested for assay use.

Cell Proliferation Assay

A serial dilution of test compound was dispensed into a 96 well blackclear bottom plate (Corning, Corning, N.Y.). For each cell line, threethousand cells were added per well in complete growth medium. Plateswere incubated for 72 hours at 37 degrees Celsius, 5% CO2, 95% humidity.At the end of the incubation period Cell Titer Blue (Promega, Madison,Wis.) was added to each well and an additional 4.5 hour incubation at 37degrees Celsius, 5% CO2, 95% humidity was performed. Plates were thenread on a BMG Fluostar Optima (BMG, Durham, N.C.) using an excitation of544 nM and an emission of 612 nM. Data was analyzed using Prism software(Graphpad, San Diego, Calif.) to calculate IC₅₀'s.

Biological Data Summary. Biochemical IC₅₀ Values of Compounds of FormulaIa.

In general, compounds 1-56 disclosed herein exhibited >50% inhibitionactivity at 0.1-2 uM concentration against Abl kinase and T315I Ablkinase.

Biological Data Summary. Whole cell IC₅₀ Values of Compounds of FormulaIa.

In general, compounds 1-56 disclosed herein exhibited >50% inhibition ofproliferation at 1-10 uM concentration against BaF/3 cells harboring wtbcr-Abl and or bcr-Abl point mutants including T315I, E255K, Y253F, andM351T.

Section 4—Important Structural Comparisons vs. Biological Activity

WO 2006/071940A2 describes inhibitors of kinases, including C-Ablkinase, B-Raf kinase, c-MET, VEGF kinase, and the HER family wherein acentral phenyl ring is unsubstituted. An example of these inhibitors isshown below, wherein the central phenyl ring is unsubstituted (R16 andR18=H). Compounds A, B and C, discussed below, are taken from WO2006/071940A2.

Representative Key Structures Example 1 (R16=2-F, R18=H), Example 5(R16=3-Me, R18=H) Compound A (R16=H, R18=H)

Example 15 (R16=2-F, R18=H) Compound B (R16=H, R18=H)

It has unexpectedly been found that inhibitors that contain R16substituents other than H have superior potency as measured by in vitrokinase inhibition and also as measured by in vivo whole cellanti-proliferation potencies in cancer cells. By way of illustration inTable 1, Example 1 of the present invention containing a 2-F moiety asthe R16 substituent is 5.5-times more potent vs. phosphorylated-Ablkinase (p-Abl) than the unsubstituted Compound A containing R16=H.Example 1 is 6.3 times more potent than Compound A vs. the T315I mutantAbl kinase, a clinical isolate of oncogenic Abl kinase found in patientswith chronic myelogenous leukemia and in whom treatment is resistant tocurrently available therapies including Gleevec® (M. E. Gorre et al,Science (2001) 293: 876; S. Branford et al, Blood (2002) 99: 3472; N.von Bubnoff et al, Lancet (2002) 359: 487) and dasatinib (N. P. Shah etal, Science (2004) 305: 399). Example 5 containing a 3-methyl moiety asthe R16 substituent is 4 times more potent vs. p-Abl kinase than theunsubstituted (R16=H) Compound A. Example 15 containing a 2-F moiety asthe R16 substituent is 8-times more potent vs. unphosphorylated-Ablkinase (u-Abl) than the unsubstituted (R16=H) Compound B (from WO2006/071940A2). Example 15 is >14-times more potent than Compound B vs.p-Abl kinase, and 18 times more potent than Compound B vs. the T315Imutant Abl kinase.

TABLE 1 u-Abl p-Abl T315I Abl R16 IC₅₀ IC₅₀ IC₅₀ Example 1 2-F 0.8 nM 4nM 6 nM Example 5 5-Me 0.7 nM 6 nM 250 nM Compound A H 1 nM 22 38Example 15 2-F 1 nM 35 nM 56 nM Compound B H 8 nM >500 nM 1,000 nMExample 4 2-F 0.7 nM 20 nM 12 nM Compound C H 1.6 nM 350 nM 160 nM

Structures of Example 4 (R16=2-F, R18=H) and Compound C(R16, R18=H)

This trend is also evident in other analogs related to those mentionedabove. As shown in Table 1, the indazolyl-containing compound Example 4containing a 2-F moiety as the R16 substituent is 2.2 times more potentthan the unsubstituted (R16=H) Compound C vs. u-Abl kinase, 18 timesmore potent than Compound C vs. p-Abl kinase, and 13 times more potentthan Compound C vs. T315I mutant Abl kinase.

This unexpected increase in potency vs. these kinases is also revealedin whole cell assays which measure the effectiveness of these Abl kinaseinhibitors to block proliferation of cells containing oncogenic forms ofAbl kinase: the fusion protein bcr-Abl kinases (C. L. Sawyers, NewEngland Journal of Medicine (1999) 340: 1330; S. Faderl et al, NewEngland Journal of Medicine (1999) 341: 164; J. B. Konopka et al,Proceeding of the National Academy of Sciences USA (1985) 82: 1810).Table 2 illustrates the increased potency of substituted R16-containingcompounds of Examples 1, 5, and 15 vs. their unsubstituted analogsCompounds A and B. The R16-substituted analogs are 2.6-4.5 times morepotent than the unsubstituted analogs in BaF3 cells expressing oncogenicbcr-abl kinase, 1.5-3.5 times more potent in BaF3 cells expressing theT315I mutant oncogenic form of bcr-abl kinase, 3.5-7.2 times more potentin BaF3 cells expressing the Y253F mutant oncogenic form of bcr-ablkinase, 4.4-6 times more potent in BaF3 cells expressing the E255Kmutant oncogenic form of bcr-abl kinase, and 3.2-4.2 times more potentin BaF3 cells expressing the M351T mutant oncogenic form of bcr-ablkinase. These five forms of bcr-abl kinase are oncogenic and arecausative of human chronic myelogenous leukemia. Moreover, the fourmutant forms of bcr-abl kinase are resistant to the currently availablebcr-abl inhibitor Gleevec®.

TABLE 2 BaF3 BaF3 Y253F BaF3 E255K M351T BaF3 wt bcr- BaF3 T315I bcr-ablbcr-abl bcr-abl R16 abl IC₅₀ bcr-abl IC₅₀ IC₅₀ IC₅₀ IC₅₀ Example 1 2-F 6 nM  8 nM 26 nM  83 nM 11 nM Example 5 5-Me  8 nM 25 nM 15 nM  62 nM10 nM Compound A H 16 nM 12 nM 108 nM  368 nM 35 nM Example 15 2-F 11 nM25 nM 86 nM 238 nM 13 nM Compound B H 49 nM 87 nM 297 nM  1,109 nM   54nM

1.-54. (canceled)
 55. A method of modulating a kinase activity of awild-type kinase species, oncogenic forms thereof, aberrant fusionproteins thereof and polymorphs of any of the foregoing, comprising thestep of contacting said species with a compound of formula Ia:

or a pharmaceutcially acceptable salt thereof, wherein E1 is phenyl andwherein the El ring is substituted with one to three R16 moieties; A isselected from the group consisting of imidazolyl, and pyrazolyl; G1 is aheteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl; G4 is a heterocyclyltaken from the group consisting of oxetanyl, azetadinyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl,morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, andhomotropanyl; the A ring is substituted at any substitutable positionwith one Al moiety, wherein A1 is selected from the group consisting of:

and wherein the symbol (**) is the point of attachment to the A ring offormula Ia; and wherein

indicates either a saturated or unsaturated bond; the A ring isoptionally substituted with one or more R2 moieties; X2 is a directbond, wherein E1 is directly linked to the NH group of formula Ia; X3 is—O—; V, V1 and V2 are each independently O or represent two hydrogensattached to the methylene carbon to which the V, V1, and V2 is attached;each Z3 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8-carbocyclyl,halogen, fluoroC1-C6alkyl wherein the alkyl moiety can be partially orfully fluorinated, cyano, hydroxyl, methoxy, oxo, (R3)₂NC(O)—,(R4)₂NC(O)—, —N(R4)C(O)R8, (R3)₂NSO₂—, (R4)₂NSO₂—, —N(R4)SO₂R5,—N(R4)SO₂R8, —(CH₂)N(R3)₂, —(CH₂),N(R4)₂, —O(CH₂),N(R4)₂,—O(CH₂)_(q)O—C₁-C₆alkyl, —N(R3)(CH₂)_(q)O—C1-C6alkyl,—N(R3)(CH₂),N(R4)₂, —O(CH₂),A5, —N(R3)(CH₂),R5, —C(O)R5, —C(O)R8, —R5,and nitro; in the event that Z3 contains an alkyl or alkylene moiety,such moieties may be further substituted by one or more C₁-C₆alkyl; eachZ4 is independently and individually selected from the group consistingof H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl,(R4)₂N—C2-C6alkyl, (R4)₂N—C2-C6alkylN(R4)—C2-C6alkyl,(R4)₂N—C2-C6alkyl-O—C2-C6alkyl, (R4)₂NC(O)—C1-C6alkyl, carboxyC1-C6alkyl-, C1-C6alkoxycarbonylC1-C6alkyl-, —C2-C6alkylN (R4)C(O)R8,R8—C(═NR3)—, —SO₂R8, —C(O)R8, and —(CH₂)_(q)R5; in the event that Z4contains an alkyl or alkylene moiety, such moieties may be furthersubstituted by one or more C1-C6alkyl; each Z6 is independently andindividually selected from the group consisting of H, C1-C6alkyl,branched C3-C7alkyl, hydroxyl, hydroxyC1-C6alkyl, hydroxyC2-C6 branchedalkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl-, C1-C6alkoxyC2-C6 branchedalkyl-, C2-C6 branched alkoxy-, C1-C6alkylthio-, (R3)₂N—, —N(R3)C(O)R8,(R4)₂N—, —R5, —N(R4)C(O)R8, —N(R3)SO₂R6, —C(O)N(R3)₂, —C(O)N(R4)₂,—C(O)R5, —SO₂N(R4)₂, —SO₂N(R5)₂, halogen, fluoroC1-C6alkyl wherein thealkyl is fully or partially fluorinated, cyano, fluoroC1-C6alkoxywherein the alkyl is fully or partially fluorinated, —O(CH₂)_(q)N(R4)₂,—N(R3)(CH₂),N(R4)₂, —O(CH₂)_(q)O—C1-C6alkyl, —O(CH₂),N(R4)₂,—N(R3)(CH₂)_(q)O—C1-C6alkyl, —N(R3)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)R5, and—N(R3)(CH₂)_(q)R5, —(NR3)_(r)R17, —(O)_(r)R17, —(S)_(r)R17,—(CH₂)_(n)R17, —R17, —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(n)O(CH₂)_(n)G1,—(CH₂)_(n)O(CH₂)_(n)G4, —(CH₂)_(n)N(R3)(CH₂)_(n)G1, and—(CH₂)_(n)N(R3)(CH₂)_(n)G4; each R2 is selected from the groupconsisting of Z3-substituted aryl, Z3-substituted G1-, Z3-substitutedG4-, C1-C6alkyl, branched C3-C8alkyl, R19 substituted C3-C8-carbocyclyl,hydroxyC1-C6alkyl-, hydroxy branched C3-C6alkyl-, hydroxy substitutedC3-C8-carbocyclyl-, cyanoC₁-C₆alkyl-, cyano substituted branchedC3-C6alkyl, cyano substituted C3-C8-carbocyclyl, (R4)₂NC(O)C1-C6alkyl-,(R4)₂NC(O) substituted branched C3-C6alkyl-, (R4)₂NC(O) substitutedC3-C8-carbocyclyl-, fluoroC1-C6alkyl wherein the alkyl is fully orpartially fluorinated, halogen, cyano, C1-C6alkoxy, andfluoroC1-C6alkoxy wherein the alkyl is fully or partially fluorinated;wherein each R3 is independently and individually selected from thegroup consisting of H, C1-C6alkyl, branched C3-C7alkyl,C3-C8-carbocyclyl, and Z3-substituted phenyl; each R4 is independentlyand individually selected from the group consisting of H, C1-C6alkyl,hydroxyC1-C6alkyl-, dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-,branched C3-C7alkyl-, branched hydroxyC1-C6alkyl-, branchedC1-C6alkoxyC1-C6alkyl-, branched dihydroxyC2-C6alkyl-, —(CH₂)_(p)N(R7)₂,—(CH₂)_(p)R5, —(CH₂)_(p)C(O)N(R7)₂, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3,C3-C8-carbocyclyl, hydroxy substituted C3-C8-carbocyclyl-, alkoxysubstituted C3-C8-carbocyclyl-, dihydroxy substitutedC3-C8-carbocyclyl-, and —(CH₂)_(n)R17; each R5 is independently andindividually selected from the group consisting of

and wherein the symbol (##) is the point of attachment of the R5 moiety;each R6 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8-carbocyclyl,phenyl, G1, and G4; each R7 is independently and individually selectedfrom the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl-,dihydroxyC2-C6alkyl-, C2-C6alkoxyC2-C6alkyl-, branched C3-C7alkyl-,branched hydroxyC2-C6alkyl-, branched C2-C6alkoxyC2-C6alkyl-, brancheddihydroxyC2-C6alkyl-, —(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3,C3-C8-carbocyclyl, hydroxy substituted C3-C8-carbocyclyl-, alkoxysubstituted C3-C8-carbocyclyl-, dihydroxy substituted C3-C8-carbocyclyl,and —(CH₂)_(n)R17; each R8 is independently and individually selectedfrom the group consisting of C1-C6alkyl, branched C3-C7alkyl,fluoroC1-C6alkyl wherein the alkyl moiety is partially or fullyfluorinated, C3-C8-carbocyclyl, Z3-substituted phenyl-, Z3-substitutedphenylC1-C6alkyl-, Z3-substituted G1, Z3-substituted G1-C1-C6alkyl-,Z2-substituted G4, Z2-substituted G4-C1-C6alkyl-, OH, C1-C6alkoxy,N(R3)₂, N(R4)₂, and R5; each R10 is independently and individuallyselected from the group consisting of CO₂H, CO₂C1-C6alkyl, —C(O)N(R4)₂,OH, C1-C6alkoxy, and —N(R4)₂; each R14 is independently and respectivelyselected from the group consisting of H, C1-C6alkyl, branchedC3-C6alkyl, and C3-C8-carbocyclyl; R16 is independently and individuallyselected from the group consisting of C1-C6alkyl, branched C3-C7alkyl,C3-C8-carbocyclyl, halogen, fluoroC1-C6alkyl wherein the alkyl moietycan be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy,fluoroC1-C6alkoxy wherein the alkyl moiety can be partially or fullyfluorinated, —N(R3)₂, —N(R4)₂, C2-C3alkynyl, and nitro; each R17 isselected from the group consisting of phenyl, naphthyl, pyrrolyl, furyl,thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, oxetanyl, azetadinyl, tetrahydrofuranyl,oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl,dioxalinyl, azepinyl, oxepinyl, diazepinyl, pyrrolidinyl, andpiperidinyl; wherein R17 can be further substituted with one or more Z2,Z3 or Z4 moieties; R19 is H or C1-C6alkyl; n is 0-6; p is 1-4; q is 2-6;r is 0 or 1; t is 1-3; and v is for
 2. 56. A method of treating anindividual suffering from a condition selected from the group consistingof cancer, hyperproliferative diseases, secondary cancer growth arisingfrom metastasis, diseases characterized by hyper-vascularization,inflammation, osteoarthritis, respiratory diseases, stroke, systemicshock, immunological diseases, cardiovascular disease and diseasescharacterized by angiogenesis, comprising the step of administering tosuch individual a compound of formula Ia:

or a pharmaceutcially acceptable salt thereof, wherein E1 is phenyl andwherein the El ring is substituted with one to three R16 moieties; A isselected from the group consisting of imidazolyl, and pyrazolyl; G1 is aheteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl; G4 is a heterocyclyltaken from the group consisting of oxetanyl, azetadinyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl,morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, andhomotropanyl; the A ring is substituted at any substitutable positionwith one Al moiety, wherein A1 is selected from the group consisting of:

and wherein the symbol (**) is the point of attachment to the A ring offormula Ia; and wherein

indicates either a saturated or unsaturated bond; the A ring isoptionally substituted with one or more R2 moieties; X2 is a directbond, wherein E1 is directly linked to the NH group of formula Ia; X3 is−O—; V, V1 and V2 are each independently O or represent two hydrogensattached to the methylene carbon to which the V, V1, and V2 is attached;each Z3 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8-carbocyclyl,halogen, fluoroC1-C6alkyl wherein the alkyl moiety can be partially orfully fluorinated, cyano, hydroxyl, methoxy, oxo, (R3)₂NC(O)—,(R4)₂NC(O)—, —N(R4)C(O)R8, (R3)₂NSO₂—, (R4)₂NSO₂—, —N(R4)SO₂R5,—N(R4)SO₂R8, —(CH₂)N(R3)₂, —(CH₂)_(n)N(R4)₂, —O(CH₂)_(q)N(R4)₂,—O(CH₂)_(q)O—C1-C6alkyl, —N(R3)(CH₂)_(q)O—C1-C6alkyl,—N(R3)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)R5, —N(R3)(CH₂)_(q)R5, —C(O)R5,—C(O)R8, —R5, and nitro; in the event that Z3 contains an alkyl oralkylene moiety, such moieties may be further substituted by one or moreC1-C6alkyl; each Z4 is independently and individually selected from thegroup consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl,C1-C6alkoxyC2-C6alkyl, (R4)₂N—C2-C6alkyl,(R4)₂N—C2-C6alkylN(R4)—C2-C6alkyl, (R4)₂N—C2-C6alkyl-O—C2-C6alkyl,(R4)₂NC(O)—C1-C6alkyl, carboxyC1-C6alkyl-,C1-C6alkoxycarbonylC1-C6alkyl-, —C2-C 6alkylN(R4)C(O)R8, R8—C(═NR3)—,—SO₂R8, —C(O)R8, and —(CH₂)_(q)R5; in the event that Z4 contains analkyl or alkylene moiety, such moieties may be further substituted byone or more C1-C6alkyl; each Z6 is independently and individuallyselected from the group consisting of H, C1-C6alkyl, branchedC3-C7alkyl, hydroxyl, hydroxyC1-C6alkyl, hydroxyC2-C6 branched alkyl,C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl-, C1-C6alkoxyC2-C6 branched alkyl-,C2-C6 branched alkoxy-, C1-C6alkylthio-, (R3)₂N—, —N(R3)C(O)R8, (R4)₂N—,—R5, —N(R4)C(O)R8, —N(R3)SO₂R6, —C(O)N(R3)₂, —C(O)N(R4)₂, —C(O)R5,—SO₂N(R4)₂, —SO₂N(R5)₂, halogen, fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated, cyano, fluoroC1-C6alkoxy wherein thealkyl is fully or partially fluorinated, —O(CH₂)_(q)N(R4)₂,—N(R3)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)O—C1-C6alkyl, —O(CH₂)_(q)N(R4)₂,—N(R3)(CH₂)_(q)O—C1-C6alkyl, —N(R3)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)R5, and—N(R3)(CH₂)_(q)R5, —(NR3)_(n)R17, —(O)_(r)R17, —(S)_(r)R17,—(CH₂)_(n)R17, —R17, —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(n)O(CH₂)_(n)G1,—(CH₂)_(n)O(CH₂)_(n)G4, —(CH₂)_(n)N(R3)(CH₂)_(n)G1, and—(CH₂)_(n)N(R3)(CH₂)_(n)G4; each R2 is selected from the groupconsisting of Z3-substituted aryl, Z3-substituted G1-, Z3-substitutedG4-, C1-C6alkyl, branched C3-C8alkyl, R19 substituted C3-C8-carbocyclyl,hydroxyC1-C6alkyl-, hydroxy branched C3-C6alkyl-, hydroxy substitutedC3-C8-carbocyclyl-, cyanoC1-C6alkyl-, cyano substituted branchedC3-C6alkyl, cyano substituted C3-C8-carbocyclyl, (R4)₂NC(O)C1-C6alkyl-,(R4)₂NC(O) substituted branched C3-C6alkyl-, (R4)₂NC(O) substitutedC3-C8-carbocyclyl-, fluoroC1-C6alkyl wherein the alkyl is fully orpartially fluorinated, halogen, cyano, C1-C6alkoxy, andfluoroC1-C6alkoxy wherein the alkyl is fully or partially fluorinated;wherein each R3 is independently and individually selected from thegroup consisting of H, C1-C6alkyl, branched C3-C7alkyl,C3-C8-carbocyclyl, and Z3-substituted phenyl; each R4 is independentlyand individually selected from the group consisting of H, C1-C6alkyl,hydroxyC1-C6alkyl-, dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-,branched C3-C7alkyl-, branched hydroxyC1-C6alkyl-, branchedC1-C6alkoxyC1-C6alkyl-, branched dihydroxyC2-C6alkyl-, —(CH₂)_(p)N(R7)₂,—(CH₂)_(p)R5, —(CH₂)_(p)C(O)N(R7)₂, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3,C3-C8-carbocyclyl, hydroxy substituted C3-C8-carbocyclyl-, alkoxysubstituted C3-C8-carbocyclyl-, dihydroxy substitutedC3-C8-carbocyclyl-, and —(CH₂)_(n)R17; each R5 is independently andindividually selected from the group consisting of

and wherein the symbol (##) is the point of attachment of the R5 moiety;each R6 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8-carbocyclyl,phenyl, G1, and G4; each R7 is independently and individually selectedfrom the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl-,dihydroxyC2-C6alkyl-, C2-C6alkoxyC2-C6alkyl-, branched C3-C7alkyl-,branched hydroxyC2-C6alkyl-, branched C2-C6alkoxyC2-C6alkyl-, brancheddihydroxyC2-C6alkyl-, —(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3,C3-C8-carbocyclyl, hydroxy substituted C3-C8-carbocyclyl-, alkoxysubstituted C3-C8-carbocyclyl-, dihydroxy substituted C3-C8-carbocyclyl,and —(CH₂)_(n)R17; each R8 is independently and individually selectedfrom the group consisting of C1-C6alkyl, branched C3-C7alkyl,fluoroC1-C6alkyl wherein the alkyl moiety is partially or fullyfluorinated, C3-C8-carbocyclyl, Z3-substituted phenyl-, Z3-substitutedphenylC1-C6alkyl-, Z3-substituted G1, Z3-substituted G1-C1-C6alkyl-,Z2-substituted G4, Z2-substituted G4-C1-C6alkyl-, OH, C1-C6alkoxy,N(R3)₂, N(R4)₂, and R5; each R10 is independently and individuallyselected from the group consisting of CO₂H, CO₂C1-C6alkyl, —C(O)N(R4)₂,OH, C1-C6alkoxy, and —N(R4)₂; each R14 is independently and respectivelyselected from the group consisting of H, C1-C6alkyl, branchedC3-C6alkyl, and C3-C8-carbocyclyl; R16 is independently and individuallyselected from the group consisting of C1-C6alkyl, branched C3-C7alkyl,C3-C8-carbocyclyl, halogen, fluoroC1-C6alkyl wherein the alkyl moietycan be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy,fluoroC1-C6alkoxy wherein the alkyl moiety can be partially or fullyfluorinated, —N(R3)₂, —N(R4)₂, C2-C3alkynyl, and nitro; each R17 isselected from the group consisting of phenyl, naphthyl, pyrrolyl, furyl,thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, oxetanyl, azetadinyl, tetrahydrofuranyl,oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl,dioxalinyl, azepinyl, oxepinyl, diazepinyl, pyrrolidinyl, andpiperidinyl; wherein R17 can be further substituted with one or more Z2,Z3 or Z4 moieties; R19 is H or C1-C6alkyl; n is 0-6; p is 1-4; q is 2-6;r is 0 or 1; t is 1-3; and v is 1 or
 2. 57. A method of treating anindividual suffering from a disease caused by c-Abl kinase, oncogenicforms thereof, aberrant fusion proteins thereof and polymorphs thereof,wherein the disease is selected from chronic myelogenous leukemia, acutelymphocytic leukemia, other myeloproliferative disorders,gastrointestinal stromal tumors, hypereosinophilic syndrome,glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lungcancers, breast cancers, kidney cancers, cervical carcinomas, metastasisof primary solid tumor to secondary sites, ocular diseases characterizedby hyperproliferation leading to blindness, retinopathies, diabeticretinopathy, age-related macular degeneration, rheumatoid arthritis,melanomas, colon cancer, thyroid cancer, a disease caused by a mutationin the RAS-RAF-MEK-ERK-MAP kinase pathway, human inflammation,rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis,sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shocksyndrome, adult respiratory distress syndrome, stroke, reperfusioninjury, neural trauma, neural ischemia, psoriasis, restenosis, chronicobstructive pulmonary disease, bone resorptive diseases,graft-versus-host reaction, Chron's disease, ulcerative colitis,inflammatory bowel disease, pyresis, and combinations thereof,comprising the step of administering to such individual a compound offormula Ia:

or a pharmaceutically acceptable salt thereof, wherein E1 is phenyl andwherein the E1 ring is substituted with one to three R16 moieties; A isselected from the group consisting of imidazolyl, and pyrazolyl; G1 is aheteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl; G4 is a heterocyclyltaken from the group consisting of oxetanyl, azetadinyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl,morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, andhomotropanyl; the A ring is substituted at any substitutable positionwith one Al moiety, wherein A1 is selected from the group consisting of:

and wherein the symbol (**) is the point of attachment to the A ring offormula Ia; and wherein

indicates either a saturated or unsaturated bond; the A ring isoptionally substituted with one or more R2 moieties; X2 is a directbond, wherein E1 is directly linked to the NH group of formula Ia; X3 is—O—; V, V1 and V2 are each independently O or represent two hydrogensattached to the methylene carbon to which the V, V1, and V2 is attached;each Z3 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8-carbocyclyl,halogen, fluoroC1-C6alkyl wherein the alkyl moiety can be partially orfully fluorinated, cyano, hydroxyl, methoxy, oxo, (R3)₂NC(O)—,(R4)₂NC(O)—, —N(R4)C(O)R8, (R3)₂NSO₂—, (R4)₂NSO₂—, —N(R4)SO₂R5,—N(R4)SO₂R8, —(CH₂)N(R3)₂, —(CH₂)_(n)N(R4)₂, —O(CH₂)_(q)N(R4)₂,—O(CH₂)_(q)O—C1-C6alkyl, —N(R3)(CH₂)_(q)O—C1-C6alkyl,—N(R3)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)R5, —N(R3)(CH₂)_(q)R5, —C(O)R5,—C(O)R8, —R5, and nitro; in the event that Z3 contains an alkyl oralkylene moiety, such moieties may be further substituted by one or moreC1-C6alkyl; each Z4 is independently and individually selected from thegroup consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl,C1-C6alkoxyC2-C6alkyl, (R4)₂N—C2-C6alkyl,(R4)₂N—C2-C6alkylN(R4)—C2-C6alkyl, (R4)₂N—C2-C6alkyl-O—C2-C6alkyl,(R4)₂NC(O)—C1-C6alkyl, carboxyC1-C6alkyl-,C1-C6alkoxycarbonylC1-C6alkyl-, —C2-C6alkylN(R4)C(O)R8, C(═NR3)—,—SO₂R8, —C(O)R8, and —(CH₂)_(q)R5; in the event that Z4 contains analkyl or alkylene moiety, such moieties may be further substituted byone or more C1-C6alkyl; each Z6 is independently and individuallyselected from the group consisting of H, C1-C6alkyl, branchedC3-C7alkyl, hydroxyl, hydroxyC1-C6alkyl, hydroxyC2-C6 branched alkyl,C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl-, C1-C6alkoxyC2-C6 branched alkyl-,C2-C6 branched alkoxy-, C1-C6alkylthio-, (R3)₂N—, —N(R3)C(O)R8, (R4)₂N—,—R5, —N(R4)C(O)R8, —N(R3)SO₂R6, —C(O)N(R3)₂, —C(O)N(R4)₂, —C(O)R5,—SO₂N(R4)₂, —SO₂N(R5)₂, halogen, fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated, cyano, fluoroC1-C6alkoxy wherein thealkyl is fully or partially fluorinated, —O(CH₂)_(q)N(R4)₂,—N(R3)(CH₂)_(g)N(R4)₂, —O(CH₂)_(q)O—C1-C6alkyl, —O(CH₂)_(g)N(R4)₂,—N(R3)(CH₂)_(q)O—C1-C6alkyl, —N(R3)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)R5, and—N(R3)(CH₂)_(q)R5, —(NR3)_(r)R17, —(O)_(r)R17, —(S)_(r)R17,—(CH₂)_(n)R17, —R17, —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(n)O(CH₂)_(n)G1,—(CH₂)_(n)O(CH₂)_(n)G4, —(CH₂)_(n)N(R3)(CH₂)_(n)G1, and—(CH₂)_(n)N(R3)(CH₂)_(n)G4; each R2 is selected from the groupconsisting of Z3-substituted aryl, Z3-substituted G1-, Z3-substitutedG4-, C1-C6alkyl, branched C3-C8alkyl, R19 substituted C3-C8-carbocyclyl,hydroxyC1-C6alkyl-, hydroxy branched C3-C6alkyl-, hydroxy substitutedC3-C8-carbocyclyl-, cyanoC1-C6alkyl-, cyano substituted branchedC3-C6alkyl, cyano substituted C3-C8-carbocyclyl, (R4)₂NC(O)C1-C6alkyl-,(R4)₂NC(O) substituted branched C3-C6alkyl-, (R4)₂NC(O) substitutedC3-C8-carbocyclyl-, fluoroC1-C6alkyl wherein the alkyl is fully orpartially fluorinated, halogen, cyano, C1-C6alkoxy, andfluoroC1-C6alkoxy wherein the alkyl is fully or partially fluorinated;wherein each R3 is independently and individually selected from thegroup consisting of H, C1-C6alkyl, branched C3-C7alkyl,C3-C8-carbocyclyl, and Z3-substituted phenyl; each R4 is independentlyand individually selected from the group consisting of H, C1-C6alkyl,hydroxyC1-C6alkyl-, dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-,branched C3-C7alkyl-, branched hydroxyC1-C6alkyl-, branchedC1-C6alkoxyC1-C6alkyl-, branched dihydroxyC2-C6alkyl-, —(CH₂)_(p)N(R7)₂,—(CH₂)_(p)R5, —(CH₂)_(p)C(O)N(R7)₂, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3,C3-C8-carbocyclyl, hydroxy substituted C3-C8-carbocyclyl-, alkoxysubstituted C3-C8-carbocyclyl-, dihydroxy substitutedC3-C8-carbocyclyl-, and —(CH₂)_(n)R17; each R5 is independently andindividually selected from the group consisting of

and wherein the symbol (##) is the point of attachment of the R5 moiety;each R6 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8-carbocyclyl,phenyl, G1, and G4; each R7 is independently and individually selectedfrom the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl-,dihydroxyC2-C6alkyl-, C2-C6alkoxyC2-C6alkyl-, branched C3-C7alkyl-,branched hydroxyC2-C6alkyl-, branched C2-C6alkoxyC2-C6alkyl-, brancheddihydroxyC2-C6alkyl-, —(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3,C3-C8-carbocyclyl, hydroxy substituted C3-C8-carbocyclyl-, alkoxysubstituted C3-C8-carbocyclyl-, dihydroxy substituted C3-C8-carbocyclyl,and —(CH₂)_(n)R17; each R8 is independently and individually selectedfrom the group consisting of C1-C6alkyl, branched C3-C7alkyl,fluoroC1-C6alkyl wherein the alkyl moiety is partially or fullyfluorinated, C3-C8-carbocyclyl, Z3-substituted phenyl-, Z3-substitutedphenylC1-C6alkyl-, Z3-substituted G1, Z3-substituted G1-C1-C6alkyl-,Z2-substituted G4, Z2-substituted G4-C1-C6alkyl-, OH, C1-C6alkoxy,N(R3)₂, N(R4)₂, and R5; each R10 is independently and individuallyselected from the group consisting of CO₂H, CO₂C1-C6alkyl, —C(O)N(R4)₂,OH, C1-C6alkoxy, and —N(R⁴)₂; each R¹⁴ is independently and respectivelyselected from the group consisting of H, C1-C6alkyl, branchedC3-C6alkyl, and C3-C8-carbocyclyl; R¹⁶ is independently and individuallyselected from the group consisting of C1-C6alkyl, branched C3-C7alkyl,C3-C8-carbocyclyl, halogen, fluoroC1-C6alkyl wherein the alkyl moietycan be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy,fluoroC1-C6alkoxy wherein the alkyl moiety can be partially or fullyfluorinated, —N(R³)₂, —N(R⁴)₂, C2-C3alkynyl, and nitro; each R¹⁷ isselected from the group consisting of phenyl, naphthyl, pyrrolyl, furyl,thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, oxetanyl, azetadinyl, tetrahydrofuranyl,oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl,dioxalinyl, azepinyl, oxepinyl, diazepinyl, pyrrolidinyl, andpiperidinyl; wherein R¹⁷ can be further substituted with one or more Z2,Z3 or Z4 moieties; R¹⁹ is H or C1-C6alkyl; n is 0-6; p is 1-4; q is 2-6;r is 0 or 1; t is 1-3; and v is 1 or
 2. 58. The method of any of claims55-57, wherein the method of administration is selected from the groupconsisting of oral, parenteral, inhalation, and subcutaneous.
 59. Themethod of claim 57, wherein the disease is selected from chronicmyelogenous leukemia, acute lymphocytic leukemia, othermyeloproliferative disorders, and hypereosinophilic syndrome.
 60. Themethod of claim 59, wherein the disease is chronic myelogenous leukemia.61. The method of claim 57, wherein the disease is selected frommetastasis of primary solid tumor to secondary sites, ovarian cancer,prostate cancer, lung cancers, breast cancers, and cervical carcinomas.62. A method of treating an individual suffering from a disease causedby c-Abl kinase, oncogenic forms thereof, aberrant fusion proteinsthereof and polymorphs thereof, wherein the disease is selected fromchronic myelogenous leukemia, acute lymphocytic leukemia, othermyeloproliferative disorders, gastrointestinal stromal tumors,hypereosinophilic syndrome, glioblastomas, ovarian cancer, pancreaticcancer, prostate cancer, lung cancers, breast cancers, kidney cancers,cervical carcinomas, metastasis of primary solid tumor secondary sites,ocular diseases characterized by hyperproliferation leading toblindness, retinopathies, diabetic retinopathy, age-related maculardegeneration, rheumatoid arthritis, melanomas, colon cancer, thyroidcancer, a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinasepathway, human inflammation, rheumatoid spondylitis, ostero-arthritis,asthma, gouty arthritis, sepsis, septic shock, endotoxic shock,Gram-negative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, stroke, reperfusion injury, neural trauma, neural ischemia,psoriasis, restenosis, chronic obstructive pulmonary disease, boneresorptive diseases, graft-versus-host reaction, Chron's disease,ulcerative colitis, inflammatory bowel disease, pyresis, andcombinations thereof, comprising the step of administering to suchindividual the compound1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureaor a pharmaceutically acceptable salt, or tautomer thereof.
 63. Themethod of claim 62, wherein the disease is selected from chronicmyelogenous leukemia, acute lymphocytic leukemia, othermyeloproliferative disorders, and hypereosinophilic syndrome.
 64. Themethod of claim 63, wherein the disease is chronic myelogenous leukemia.65. The method of claim 62, wherein the disease is selected frommetastasis of primary solid tumor to secondary sites, ovarian cancer,prostate cancer, lung cancers, breast cancers, and cervical carcinomas.66. A method of treating an individual suffering from a disease causedby c-Abl kinase, oncogenic forms thereof, aberrant fusion proteinsthereof and polymorphs thereof, wherein the disease is selected fromchronic myelogenous leukemia, acute lymphocytic leukemia, othermyeloproliferative disorders, gastrointestinal stromal tumors,hypereosinophilic syndrome, glioblastomas, ovarian cancer, pancreaticcancer, prostate cancer, lung cancers, breast cancers, kidney cancers,cervical carcinomas, metastasis of primary solid tumor secondary sites,ocular diseases characterized by hyperproliferation leading toblindness, retinopathies, diabetic retinopathy, age-related maculardegeneration, rheumatoid arthritis, melanomas, colon cancer, thyroidcancer, a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinasepathway, human inflammation, rheumatoid spondylitis, ostero-arthritis,asthma, gouty arthritis, sepsis, septic shock, endotoxic shock,Gram-negative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, stroke, reperfusion injury, neural trauma, neural ischemia,psoriasis, restenosis, chronic obstructive pulmonary disease, boneresorptive diseases, graft-versus-host reaction, Chron's disease,ulcerative colitis, inflammatory bowel disease, pyresis, andcombinations thereof, comprising the step of administering to suchindividual the compound1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)ureaor a pharmaceutically acceptable salt, or tautomer thereof.
 67. Themethod of claim 66, wherein the disease is selected from chronicmyelogenous leukemia, acute lymphocytic leukemia, othermyeloproliferative disorders, and hypereosinophilic syndrome.
 68. Themethod of claim 67, wherein the disease is chronic myelogenous leukemia.69. The method of claim 66, wherein the disease is selected frommetastasis of primary solid tumor to secondary sites, ovarian cancer,prostate cancer, lung cancers, breast cancers, and cervical carcinomas.70. A method of treating an individual suffering from a disease causedby c-Abl kinase, oncogenic forms thereof, aberrant fusion proteinsthereof and polymorphs thereof, wherein the disease is selected fromchronic myelogenous leukemia, acute lymphocytic leukemia, othermyeloproliferative disorders, gastrointestinal stromal tumors,hypereosinophilic syndrome, glioblastomas, ovarian cancer, pancreaticcancer, prostate cancer, lung cancers, breast cancers, kidney cancers,cervical carcinomas, metastasis of primary solid tumor secondary sites,ocular diseases characterized by hyperproliferation leading toblindness, retinopathies, diabetic retinopathy, age-related maculardegeneration, rheumatoid arthritis, melanomas, colon cancer, thyroidcancer, a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinasepathway, human inflammation, rheumatoid spondylitis, ostero-arthritis,asthma, gouty arthritis, sepsis, septic shock, endotoxic shock,Gram-negative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, stroke, reperfusion injury, neural trauma, neural ischemia,psoriasis, restenosis, chronic obstructive pulmonary disease, boneresorptive diseases, graft-versus-host reaction, Chron's disease,ulcerative colitis, inflammatory bowel disease, pyresis, andcombinations thereof, comprising the step of administering to suchindividual the compound1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)ureaor a pharmaceutically acceptable salt, or tautomer thereof.
 71. Themethod of claim 70, wherein the disease is selected from chronicmyelogenous leukemia, acute lymphocytic leukemia, othermyeloproliferative disorders, and hypereosinophilic syndrome.
 72. Themethod of claim 71, wherein the disease is chronic myelogenous leukemia.73. The method of claim 70, wherein the disease is selected frommetastasis of primary solid tumor to secondary sites, ovarian cancer,prostate cancer, lung cancers, breast cancers, and cervical carcinomas.74. A method of treating an individual suffering from a disease causedby c-Abl kinase, oncogenic forms thereof, aberrant fusion proteinsthereof and polymorphs thereof, wherein the disease is selected fromchronic myelogenous leukemia, acute lymphocytic leukemia, othermyeloproliferative disorders, gastrointestinal stromal tumors,hypereosinophilic syndrome, glioblastomas, ovarian cancer, pancreaticcancer, prostate cancer, lung cancers, breast cancers, kidney cancers,cervical carcinomas, metastasis of primary solid tumor secondary sites,ocular diseases characterized by hyperproliferation leading toblindness, retinopathies, diabetic retinopathy, age-related maculardegeneration, rheumatoid arthritis, melanomas, colon cancer, thyroidcancer, a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinasepathway, human inflammation, rheumatoid spondylitis, ostero-arthritis,asthma, gouty arthritis, sepsis, septic shock, endotoxic shock,Gram-negative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, stroke, reperfusion injury, neural trauma, neural ischemia,psoriasis, restenosis, chronic obstructive pulmonary disease, boneresorptive diseases, graft-versus-host reaction, Chron's disease,ulcerative colitis, inflammatory bowel disease, pyresis, andcombinations thereof, comprising the step of administering to suchindividual the compound1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)ureaor a pharmaceutically acceptable salt, or tautomer thereof.
 75. Themethod of claim 74, wherein the disease is selected from chronicmyelogenous leukemia, acute lymphocytic leukemia, othermyeloproliferative disorders, and hypereosinophilic syndrome.
 76. Themethod of claim 75, wherein the disease is chronic myelogenous leukemia.77. The method of claim 74, wherein the disease is selected frommetastasis of primary solid tumor to secondary sites, ovarian cancer,prostate cancer, lung cancers, breast cancers, and cervical carcinomas.78. A method of treating an individual suffering from a disease causedby c-Abl kinase, oncogenic forms thereof, aberrant fusion proteinsthereof and polymorphs thereof, wherein the disease is selected fromchronic myelogenous leukemia, acute lymphocytic leukemia, othermyeloproliferative disorders, gastrointestinal stromal tumors,hypereosinophilic syndrome, glioblastomas, ovarian cancer, pancreaticcancer, prostate cancer, lung cancers, breast cancers, kidney cancers,cervical carcinomas, metastasis of primary solid tumor secondary sites,ocular diseases characterized by hyperproliferation leading toblindness, retinopathies, diabetic retinopathy, age-related maculardegeneration, rheumatoid arthritis, melanomas, colon cancer, thyroidcancer, a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinasepathway, human inflammation, rheumatoid spondylitis, ostero-arthritis,asthma, gouty arthritis, sepsis, septic shock, endotoxic shock,Gram-negative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, stroke, reperfusion injury, neural trauma, neural ischemia,psoriasis, restenosis, chronic obstructive pulmonary disease, boneresorptive diseases, graft-versus-host reaction, Chron's disease,ulcerative colitis, inflammatory bowel disease, pyresis, andcombinations thereof, comprising the step of administering to suchindividual the compound1-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureaor a pharmaceutically acceptable salt, or tautomer thereof.
 79. Themethod of claim 78, wherein the disease is selected from chronicmyelogenous leukemia, acute lymphocytic leukemia, othermyeloproliferative disorders, and hypereosinophilic syndrome.
 80. Themethod of claim 79, wherein the disease is chronic myelogenous leukemia.81. The method of claim 78, wherein the disease is selected frommetastasis of primary solid tumor to secondary sites, ovarian cancer,prostate cancer, lung cancers, breast cancers, and cervical carcinomas.